METHODS FOR TREATING PATIENTS WITH HETEROZYGOUS FAMILIAL HYPERCHOLESTEROLEMIA (heFH) WITH AN ANTI-PCSK9 ANTIBODY

ABSTRACT

The present invention provides methods for treating hypercholesterolemia. The methods of the present invention comprise administering to patients with heterozygous familial hypercholesterolemia a pharmaceutical composition comprising a PCSK9 inhibitor. In certain embodiments, the PCSK9 inhibitor is an anti-PCSK9 antibody such as the exemplary antibody referred to herein as mAb316P. The methods of the present invention are useful for treating patients with heterozygous familial hypercholesterolemia who are not adequately controlled by maximum tolerated dose statin therapy with or without other lipid lowering therapy.

RELATED APPLICATIONS

This application is a continuation of U.S. patent application Ser. No.16/707,492, filed Dec. 9, 2019, which is a continuation of U.S. patentapplication Ser. No. 14/801,384, filed Jul. 16, 2015, now U.S. Pat. No.10,544,232, which claims the benefit of U.S. Provisional Application No.62/080,717, filed on Nov. 17, 2014, U.S. Provisional Application No.62/043,144, filed on Aug. 28, 2014, U.S. Provisional Application No.62/025,362, filed on Jul. 16, 2014, and European Patent Application No.15305419.2, filed on Mar. 23, 2015, the contents of which areincorporated herein by reference in their entirety.

FIELD OF THE INVENTION

The present invention relates to the field of therapeutic treatments ofdiseases and disorders that are associated with elevated levels oflipids and lipoproteins. More specifically, the invention relates to theuse of PCSK9 inhibitors to treat patients with heterozygous familialhypercholesterolemia who are not adequately controlled by maximumtolerated dose statin therapy with or without other lipid loweringtherapy.

BACKGROUND

Heterozygous familial hypercholesterolemia (heFH) is a hereditary lipidmetabolism disorder that predisposes affected individuals tocardiovascular (CV) disease. Patients with heFH typically have very highlow-density lipoprotein cholesterol (LDL-C) levels—often >190 mg/dL atthe time of diagnosis—that are associated with high risk for prematureCV disease. Findings from observational studies have shown that the riskof coronary heart disease (CHD) is reduced in heFH patients receivingstatin therapy; however, even with treatment, the risk of CHD is stillgreater in heFH patients than in the general population. Despite theavailability of lipid-lowering therapy (LLT), approximately 80% ofpatients with heFH do not reach the recommended levels of LDL-C. Giventhe increased CV risk in the heFH population, there is a need to providepatients with more intensive cholesterol-lowering therapy.

Current LDL-C lowering medications include statins, cholesterolabsorption inhibitors (e.g., ezetimibe [EZE]), fibrates, niacin, andbile acid sequestrants. Statins are the most commonly prescribed, asthey have shown a greater ability to lower LDL-C and reduce CHD events.However, many patients at risk of cardiovascular disease (CVD) havepoorly controlled low-density lipoprotein cholesterol (LDL-C) despitestatin therapy.

BRIEF SUMMARY OF THE INVENTION

The present invention provides methods for treatinghypercholesterolemia. In particular, the methods of the presentinvention are useful for treating patients with heterozygous familialhypercholesterolemia who are not adequately controlled by maximumtolerated dose statin therapy with or without other lipid loweringtherapy.

According to one aspect, the methods of the present invention compriseadministering one or more doses of a PCSK9 inhibitor to a patient withheterozygous familial hypercholesterolemia who is not adequatelycontrolled by maximum tolerated dose statin therapy with or withoutother lipid lowering therapy (i.e., hypercholesterolemia that is notadequately controlled by maximum tolerated dose statin therapy in theabsence of a PCSK9 inhibitor, with or without other lipid modifyingtherapy). According to certain embodiments of the present invention, thePCSK9 inhibitor is administered to the patient with heterozygousfamilial hypercholesterolemia as an add-on therapy to the patient'sexisting statin therapy with or without other lipid lowering therapy.

According to another aspect, the methods of the present inventioncomprise selecting a patient with heterozygous familialhypercholesterolemia who is not adequately controlled by maximumtolerated dose statin therapy with or without other lipid loweringtherapy (e.g., a maximum tolerated dose statin therapy), andadministering to the patient one or more doses of a PCSK9 inhibitor incombination with (i.e., “on top of”) the statin therapy.

Another aspect of the invention includes a method for treating a patientwith heterozygous familial hypercholesterolemia (heFH) who is notadequately controlled by maximum tolerated dose statin therapy with orwithout other lipid lowering therapy by administering one or more dosesof a proprotein convertase subtilisin/kexin type 9 (PCSK9) inhibitor tothe patient, wherein the patient exhibits inadequate control of thehypercholesterolemia despite treatment with the maximum tolerated dosestatin therapy with or without other lipid lowering therapy in theabsence of the PCSK9 inhibitor.

Another aspect of the invention includes a method for reducinglow-density lipoprotein cholesterol (LDL-C) in a patient withheterozygous familial hypercholesterolemia (heFH) who is not adequatelycontrolled by maximum tolerated dose statin therapy with or withoutother lipid lowering therapy by administering one or more doses of aproprotein convertase subtilisin/kexin type 9 (PCSK9) inhibitor to thepatient, wherein the patient exhibits inadequate control of thehypercholesterolemia despite treatment with the maximum tolerated dosestatin therapy with or without other lipid lowering therapy in theabsence of the PCSK9 inhibitor.

Another aspect of the invention includes a method for treatinghypercholesterolemia in a patient with heterozygous familialhypercholesterolemia (heFH) who is not adequately controlled by maximumtolerated dose statin therapy with or without other lipid loweringtherapy by administering one or more doses of a proprotein convertasesubtilisin/kexin type 9 (PCSK9) inhibitor to the patient, wherein thepatient exhibits inadequate control of the hypercholesterolemia despitetreatment with the maximum tolerated dose statin therapy with or withoutother lipid lowering therapy in the absence of the PCSK9 inhibitor.

Another aspect of the invention includes a method for improving theserum level of one or more lipid components in a patient withheterozygous familial hypercholesterolemia (heFH) who is not adequatelycontrolled by maximum tolerated dose statin therapy with or withoutother lipid lowering therapy by administering one or more doses of aproprotein convertase subtilisin/kexin type 9 (PCSK9) inhibitor to thepatient, wherein the patient exhibits inadequate control of the lipidcomponent despite treatment with the maximum tolerated dose statintherapy with or without other lipid lowering therapy in the absence ofthe PCSK9 inhibitor. In certain aspects, the invention provides adecrease in the serum level of a lipid component selected from the groupconsisting of LDL-C, Apo B, non-HDL-C, total cholesterol, Lp(a), andtriglycerides. In certain aspects, the invention provides an increase inthe serum level of a lipid component selected from the group consistingof HDL-C and Apo A1.

In certain aspects of the invention, the diagnosis of heFH is made byeither genotyping or by clinical criteria. In some aspects, the clinicalcriteria is either the Simon Broome Register Diagnostic Criteria forHeterozygous Familial Hypercholesterolemia, or the WHO/Dutch LipidNetwork criteria with a score >8.

In certain aspects of the invention, the PCSK9 inhibitor is an antibodyor an antigen-binding fragment thereof that specifically binds PCSK9.

In certain aspects of the invention, the antibody or antigen-bindingfragment thereof comprises the heavy and light chain complementaritydetermining regions (CDRs) of a heavy chain variable region/light chainvariable region (HCVR/LCVR) amino acid sequence pair selected from thegroup consisting of SEQ ID NOs: 1/6 and 11/15. In some aspects, theantibody or antigen-binding fragment thereof comprises heavy and lightchain CDR amino acid sequences having SEQ ID NOs:12, 13, 14, 16, 17, and18. In some aspects, the antibody or antigen-binding fragment thereofcomprises an HCVR having the amino acid sequence of SEQ ID NO:11 and anLCVR having the amino acid sequence of SEQ ID NO:15. In some aspects,the antibody or antigen-binding fragment thereof comprises heavy andlight chain CDR amino acid sequences having SEQ ID NOs:2, 3, 4, 7, 8,and 10. In some aspects, the antibody or antigen-binding fragmentthereof comprises an HCVR having the amino acid sequence of SEQ ID NO:1and an LCVR having the amino acid sequence of SEQ ID NO:6.

In certain aspects of the invention, the antibody or antigen-bindingfragment thereof binds to the same epitope on PCSK9 as an antibodycomprising heavy and light chain CDR amino acid sequences having SEQ IDNOs:12, 13, 14, 16, 17, and 18; or SEQ ID NOs: 2, 3, 4, 7, 8, and 10.

In certain aspects of the invention, the antibody or antigen-bindingfragment thereof competes for binding to PCSK9 with an antibodycomprising heavy and light chain CDR amino acid sequences having SEQ IDNOs:12, 13, 14, 16, 17, and 18; or SEQ ID NOs: 2, 3, 4, 7, 8, and 10.

In certain aspects of the invention, the antibody or antigen-bindingfragment thereof that specifically binds PCSK9 is administered to thepatient at a dose of about 75 mg at a frequency of once every two weeks.In some aspects, the about 75 mg dose is maintained if the patient'sLDL-C measured after five or more doses is <70 mg/dL. In some aspects,the about 75 mg dose is discontinued if the patient's LDL-C measuredafter five or more doses remains ≥70 mg/dL, and the antibody orantigen-binding fragment thereof that specifically binds PCSK9 issubsequently administered to the patient at a dose of about 150 mg at afrequency of once every two weeks. In some aspects, the antibody orantigen-binding fragment thereof that specifically binds PCSK9 isadministered to the patient at a dose of about 150 mg at a frequency ofonce every two weeks.

In certain aspects of the invention, the PCSK9 inhibitor is administeredto the patient in combination with the maximum tolerated dose statintherapy. In some aspects, the maximum tolerated dose statin therapycomprises a daily dose of about 40 mg to about 80 mg of atorvastatin. Insome aspects, the maximum tolerated dose statin therapy comprises adaily dose of about 20 mg to about 40 mg of rosuvastatin. In someaspects, the maximum tolerated dose statin therapy comprises a dailydose of about 80 mg of simvastatin.

In certain aspects of the invention, the PCSK9 inhibitor is administeredto the patient in combination with the other lipid lowering therapy.

In certain aspects of the invention, the method improves at least onehypercholesterolemia-associated parameter selected from the groupconsisting of: (a) reduction of the patient's low density lipoproteincholesterol (LDL-C) by at least 40%; (b) reduction of the patient'sapolipoprotein B (ApoB) by at least 30%; (c) reduction of the patient'snon-high density lipoproprotein cholesterol (non-HDL-C) by at least 40%;(d) reduction of the patient's total cholesterol by at least 20%; (e)increase of the patient's high density lipoprotein cholesterol (HDL-C)by at least 3%; (f) reduction of the patient's triglycerides by at least5%; (g) reduction of the patient's lipoprotein a (Lp(a)) by at least20%; and (h) increase of the patient's apolipoprotein Al by at least 1%.

Other embodiments of the present invention will become apparent from areview of the ensuing detailed description.

BRIEF DESCRIPTION OF THE FIGURES

FIG. 1 is a graphic representation of the study design for ODYSSEY FH I(Example 2)

FIG. 2 is a graph showing the calculated LDL-C LS mean percent changefrom baseline over time for treatment with alirocumab or placebo in theITT population in the ODYSSEY FH I study (Example 2). The least-squares(LS) means and standard errors (SD) are taken from MMRM (mixed-effectmodel with repeated measures) analysis.

FIG. 3 is a graphic representation of the study design for ODYSSEY FH II(Example 3)

FIG. 4 is a graph showing the LDL-C LS mean (+/−SE) percent change frombaseline over time for the ITT population in the ODYSSEY FH II study(Example 3). The Least-squares (LS) means and standard errors (SE) takenfrom MMRM (mixed-effect model with repeated measures) analysis.

FIG. 5 is a graph showing the LDL-C LS mean (+/−SE) percent change frombaseline during efficacy treatment period over time for the mITTPopulation in the ODYSSEY FH II study (Example 3).

FIG. 6 is a graphic representation of the study design for ODYSSEY HIGHFH (Example 4). Labels in the study design are defined as follows: FU:follow up; HeFH, heterozygous familial hypercholesterolemia; LLT,lipid-lowering therapy; OLE, open-label extension.

FIG. 7 is a graph showing the calculated LDL-C LS mean percent changefrom baseline over time for treatment with alirocumab or placebo in theITT population in the ODYSSEY HIGH FH study (Example 4). Theleast-squares (LS) means and standard errors (SE) are taken from MMRM(mixed-effect model with repeated measures) analysis.

FIG. 8 is a graph showing the LS mean (SE) calculated LDL-C valuesversus time for the ODYSSEY FH I and FH II studies. The values indictedon the graph are the LS mean % change from baseline to week 24 and week52.

FIG. 9 is a graph showing the LS mean (SE) calculated LDL-C valuesversus time for the ODYSSEY FH I and FH II studies. The values indicatedbelow the graph are the numbers of patients analyzed at the varioustimepoints.

FIG. 10 is a graph showing LDL-C levels over time in alirocumab patientsaccording to whether dose was increased to 150 mg Q2W or maintained at75 mg Q2W (ITT analysis).

FIGS. 11A, 11B, and 11C depict charts showing subgroup analysis of LDL-Creductions from baseline to week 24 (alirocumab vs. placebo) accordingto demographics and baseline characteristics (FIG. 11A), statin/LLT use(FIG. 11B), and baseline lipids (FIG. 110) (ITT analysis; pooled datafrom FH I and FH II). Moderate chronic kidney disease (CKD) was definedas an estimated glomerular filtration rate of ≥30 and ≤60 mL/min/1.73m2. In FH I, 20/323 and 9/163 patients in alirocumab and placebo armshad moderate CKD at baseline. Corresponding values in FH II were 2/167and 1/82. “High intensity” statin dose refers to atorvastatin 40-80 mgor rosuvastatin 20-40 mg.

FIG. 12 is a graphic representation of patient disposition in theODYSSEY HIGH FH study.

FIG. 13 is a graph showing the percent change from baseline to week 24in LDL-C levels by individual patients in the ODYSSEY HIGH FH study. Allpatients were on a background statin (at the maximum tolerated level). Asubset of patients also received a further lipid lowering therapy.

FIGS. 14A-14B depict graphs showing the LS mean (SE) calculated LDL-Cvalues versus time for the ODYSSEY HIGH FH study. In FIG. 14A, thevalues indicted on the graph are the LS mean % values (in mg/dL) at week24 and week 52. In FIG. 14B, the values indicated on the graph are theLS mean % values (in mg/dL) at week 24 and week 78. All patients were ona background statin (at the maximum tolerated level). A subset ofpatients also received a further lipid lowering therapy.

DETAILED DESCRIPTION

Before the present invention is described, it is to be understood thatthis invention is not limited to the particular methods and experimentalconditions described, as such methods and conditions may vary. It isalso to be understood that the terminology used herein is for thepurpose of describing particular embodiments only, and is not intendedto be limiting, since the scope of the present invention will be limitedonly by the appended claims.

Unless defined otherwise, all technical and scientific terms used hereinhave the same meaning as commonly understood by one of ordinary skill inthe art to which this invention belongs. As used herein, the term“about,” when used in reference to a particular recited numerical value,means that the value may vary from the recited value by no more than 1%.For example, as used herein, the expression “about 100” includes 99 and101 and all values in between (e.g., 99.1, 99.2, 99.3, 99.4, etc.).

Although any methods and materials similar or equivalent to thosedescribed herein can be used in the practice of the present invention,the preferred methods and materials are now described. All publicationsmentioned herein are incorporated herein by reference to describe intheir entirety.

Heterozygous Familial Hypercholesterolemia Not Adequately Controlled byMaximum Tolerated Dose Statin Therapy With or Without Other LipidLowering Therapy

The present invention relates generally to methods and compositions fortreating patients with heterozygous familial hypercholesterolemia whoare not adequately controlled by maximum tolerated dose statin therapywith or without other lipid lowering therapy, i.e., hypercholesterolemianot adequately controlled by a therapeutic regimen comprising a dailymaximum tolerated dose of a statin. As used herein, the expression “notadequately controlled,” in reference to hypercholesterolemia, means thatthe patient's serum low-density lipoprotein cholesterol (LDL-C)concentration, total cholesterol concentration, and/or triglycerideconcentration is not reduced to a recognized, medically-acceptable level(taking into account the patient's relative risk of coronary heartdisease) after at least 4 weeks on a therapeutic regimen comprising astable daily dose of a statin. For example, “a patient withhypercholesterolemia that is not adequately controlled by a statin”includes patients with a serum LDL-C concentration of greater than about70 mg/dL, 100 mg/dL, 130 mg/dL, 140 mg/dL, or more (depending on thepatient's underlying risk of heart disease) after the patient has beenon a stable daily statin regimen for at least 4 weeks.

According to certain embodiments, the patients with heterozygousfamilial hypercholesterolemia who are not adequately controlled bymaximum tolerated dose statin therapy with or without other lipidlowering therapy who are treatable by the methods of the presentinvention have hypercholesterolemia (e.g., a serum LDL-C concentrationof greater than or equal to 70 mg/dL in patients with a history ofdocumented cardiovascular disease or a serum LDL-C 100 mg/dL in patientswithout a history of documented cardiovascular disease) despite taking astable daily dose of a statin (with or without other lipid modifyingtherapy) for at least 4 weeks, 5 weeks, 6 weeks, or more. In certainembodiments, the heterozygous familial hypercholesterolemia patient'shypercholesterolemia is inadequately controlled by a maximum tolerateddose statin therapy (also referred to herein as “a daily maximumtolerated dose therapeutic statin regimen”).

As used herein, “maximum tolerated dose statin therapy” means atherapeutic regimen comprising the administration of daily dose of astatin that is the maximally tolerated dose for a particular patient.Maximally tolerated dose means the highest dose of statin that can beadministered to a patient without causing unacceptable adverse sideeffects in the patient. Maximum tolerated dose statin therapy includes,but is not limited to, e.g., 40-80 mg of atorvastatin daily, 20-40 mg ofrosuvastatin daily, or 80 mg of simvastatin (if already on this dosefor >1 year). However, patients not able to tolerate the above statindoses could take a lower dose of daily atorvastatin, rosuvastatin, orsimvastatin provided there was an acceptable reason for not using thehigher dose. Some examples of acceptable reasons for a patient taking alower statin dose include: adverse effects on higher doses, advancedage, low body mass index (BMI), regional practices, local prescribinginformation, concomitant medications, and comorbid conditions such asimpaired glucose tolerance/impaired fasting glucose.

The present invention also includes methods for treating patients withheterozygous familial hypercholesterolemia that are not adequatelycontrolled by maximum tolerated dose statin therapy with or withoutother lipid lowering therapy comprising daily administration of otherstatins such as cerivastatin, pitavastatin, fluvastatin, lovastatin, andpravastatin.

Patient Selection

The present invention includes methods and compositions useful fortreating patients with heterozygous familial hypercholesterolemia whoare not adequately controlled by maximum tolerated dose statin therapywith or without other lipid lowering therapy.

Diagnosis of heFH must be made either by genotyping or by clinicalcriteria. For those patients not genotyped, the clinical diagnosis maybe based on either the Simon Broome criteria with a criteria fordefinite FH or the WHO/Dutch Lipid Network criteria with a score >8points.

According to the Simon Broome Register Diagnostic Criteria forHeterozygous Familial Hypercholesterolemia, definite familialhypercholesterolemia is defined as: 1) total-C>6.7 mmol/l (260 mg/dL) orLDL cholesterol above 4.0 mmol/l (155 mg/dL) in a child<16 years orTotal-C>7.5 mmol/l (290 mg/dL) or LDL cholesterol above 4.9 mmol/l (190mg/dL) in an adult. (Levels either pre-treatment or highest ontreatment); plus either A) tendon xanthomas in patient, or in 1st degreerelative (parent, sibling, child), or in 2nd degree relative(grandparent, uncle, aunt); or B) DNA-based evidence of an LDL receptormutation or familial defective apo B-100.

According to the Simon Broome Register Diagnostic Criteria forHeterozygous Familial Hypercholesterolemia, possible familialhypercholesterolemia is defined as: 1) total-C>6.7 mmol/l (260 mg/dL) orLDL cholesterol above 4.0 mmol/l (155 mg/dL) in a child<16 years orTotal-C>7.5 mmol/l (290 mg/dL) or LDL cholesterol above 4.9 mmol/l (190mg/dL) in an adult. (Levels either pre-treatment or highest ontreatment); and at least one of the following: A) family history of MIbelow 50 years of age in 2nd degree relative or below 60 years of age in1st degree relative; and B) family history of raised cholesterols>7.5mmol/l (290 mg/dL) in adult 1st or 2nd degree relative or >6.7 mmol/l(260 mg/dL) in child or sibling under 16 years of age.

The WHO Criteria (Dutch Lipid Network clinical criteria) for diagnosisof Heterozygous Familial Hypercholesterolemia (heFH) is set forth in theExamples, such as in Table 2.

According to certain embodiments, the heterozygous familialhypercholesterolemia patient may be selected on the basis of having oneor more additional risk factors selected from the group consisting ofage (e.g., older than 40, 45, 50, 55, 60, 65, 70, 75, or 80 years),race, national origin, gender (male or female), exercise habits (e.g.,regular exerciser, non-exerciser), other preexisting medical conditions(e.g., type-II diabetes, high blood pressure, myocardial infarction,ischemic stroke, etc.), and current medication status (e.g., currentlytaking beta blockers, niacin, ezetimibe, fibrates, omega-3 fatty acids,bile acid resins, etc.).

According to the present invention, heterozygous familialhypercholesterolemia patients may be selected on the basis of acombination of one or more of the foregoing selection criteria ortherapeutic characteristics.

Administration of a PCSK9 Inhibitor as Add-On Therapy to MaximumTolerated Dose Statin Therapy

The present invention includes methods wherein a heterozygous familialhypercholesterolemia patient who is not adequately controlled by maximumtolerated dose statin therapy with or without other lipid loweringtherapy in the absence of a PCSK9 inhibitor is administered a PCSK9inhibitor according to a particular dosing amount and frequency, andwherein the PCSK9 inhibitor is administered as an add-on to thepatient's therapeutic statin regimen. For example, according to certainembodiments, if a patient with heterozygous familialhypercholesterolemia who is not adequately controlled by maximumtolerated dose statin therapy with or without other lipid loweringtherapy comprising, e.g., 40-80 mg of atorvastatin, the patient withheterozygous familial hypercholesterolemia may be administered a PCSK9inhibitor at a particular amount and dosing interval while the patientcontinues his or her stable daily therapeutic statin regimen.

The methods of the present invention include add-on therapeutic regimenswherein the PCSK9 inhibitor is administered as add-on therapy to thesame stable daily maximum tolerated dose therapeutic statin regimen(i.e., same dosing amount of statin) that the heterozygous familialhypercholesterolemia risk patient was on prior to receiving the PCSK9inhibitor. In other embodiments, the PCSK9 inhibitor is administered asadd-on therapy to a daily maximum tolerated dose therapeutic statinregimen comprising a statin in an amount that is more than or less thanthe dose of statin the patient was on prior to receiving the PCSK9inhibitor. For example, after starting a therapeutic regimen comprisinga PCSK9 inhibitor administered at a particular dosing frequency andamount, the daily dose of statin administered or prescribed to thepatient may (a) stay the same, (b) increase, or (c) decrease (e.g.,up-titrate or down-titrate) in comparison to the daily statin dose thehigh cardiovascular risk patient was taking before starting the PCSK9inhibitor therapeutic regimen, depending on the therapeutic needs of thepatient.

Therapeutic Efficacy

The methods of the present invention will result in the improvement inthe serum level of one or more lipid components selected from the groupconsisting of LDL-C, ApoB, non-HDL-C, total cholesterol, HDL-C,triglycerides, Apo A-1, and Lp(a). For example, according to certainembodiments of the present invention, administration of a pharmaceuticalcomposition comprising a PCSK9 inhibitor to a heterozygous familialhypercholesterolemia patient who is not adequately controlled by astable daily maximum tolerated dose therapeutic statin regimen (e.g.,administration of the PCSK9 inhibitor on top of the patient's maximumtolerated dose statin therapy) will result in a mean percent reductionfrom baseline in serum low density lipoprotein cholesterol (LDL-C) of atleast about 40%, 41%, 42%, 43%, 44%, 45%, 46%, 47%, 48%, 49%, 50%, 51%,52%, 53%, 54%, 55%, or greater; a mean percent reduction from baselinein ApoB of at least about 30%, 31%, 32%, 33%, 34%, 35%, 36%, 37%, 38%,39%, 40%, 41%, 42%, 43%, 44%, 45%,or greater; a mean percent reductionfrom baseline in non-HDL-C of at least about 40%, 41%, 42%, 43%, 44%,45%, 46%, 47%, 48%, 49%, 50%, 51%, 52%, 53%, 54%, 55%, or greater; amean percent reduction from baseline in total cholesterol of at leastabout 20%, 21%, 22%, 23%, 24%, 25%, 26%, 27%, 28%, 29%, 30%, 31%, 32%,33%, 34%, 35%, or greater; a mean percent increase from baseline inHDL-C of at least about 1%, 2%, 3%, 4%, 5%, 6%, 7%, 8%, 9%, 10%, 11%,12%, 13%, 14%, 15% or greater; a mean percent reduction from baseline intriglycerides of at least about 2%, 3%, 4%, 5%, 6%, 7%, 8%, 9%, 10%,11%, 12%, 13%, 14%, 15%, or greater; a mean percent increase frombaseline in Apo A-1 of at least about 1%, 2%, 3%, 4%, 5%, 6%, 7%, 8%,9%, 10%, or greater; and/or a mean percent reduction from baseline inLp(a) of at least about 20%, 21%, 22%, 23%, 24%, 25%, 26%, 27%, 28%,29%, 30%, 31%, 32%, 33%, 34%, 35%, or greater.

PCSK9 Inhibitors

The methods of the present invention comprise administering to a patientwith heterozygous familial hypercholesterolemia who is not adequatelycontrolled by maximum tolerated dose statin therapy with or withoutother lipid lowering therapy a therapeutic composition comprising aPCSK9 inhibitor. As used herein, a “PCSK9 inhibitor” is any agent thatbinds to or interacts with human PCSK9 and inhibits the normalbiological function of PCSK9 in vitro or in vivo. Non-limiting examplesof categories of PCSK9 inhibitors include small molecule PCSK9antagonists, peptide-based PCSK9 antagonists (e.g., “peptibody”molecules), and antibodies or antigen-binding fragments of antibodiesthat specifically bind human PCSK9.

The term “human proprotein convertase subtilisin/kexin type 9” or “humanPCSK9” or “hPCSK9”, as used herein, refers to PCSK9 having the nucleicacid sequence shown in SEQ ID NO:197 and the amino acid sequence of SEQID NO:198, or a biologically active fragment thereof.

The term “antibody”, as used herein, is intended to refer toimmunoglobulin molecules comprising four polypeptide chains, two heavy(H) chains and two light (L) chains inter-connected by disulfide bonds,as well as multimers thereof (e.g., IgM). Each heavy chain comprises aheavy chain variable region (abbreviated herein as HCVR or VH) and aheavy chain constant region. The heavy chain constant region comprisesthree domains, CH1, CH2 and CH3. Each light chain comprises a lightchain variable region (abbreviated herein as LCVR or VL) and a lightchain constant region. The light chain constant region comprises onedomain (CL1). The VH and VL regions can be further subdivided intoregions of hypervariability, termed complementarity determining regions(CDRs), interspersed with regions that are more conserved, termedframework regions (FR). Each VH and VL is composed of three CDRs andfour FRs, arranged from amino-terminus to carboxy-terminus in thefollowing order: FR1, CDR1, FR2, CDR2, FR3, CDR3, FR4. In differentembodiments of the invention, the FRs of the anti-PCSK9 antibody (orantigen-binding portion thereof) may be identical to the human germlinesequences, or may be naturally or artificially modified. An amino acidconsensus sequence may be defined based on a side-by-side analysis oftwo or more CDRs.

The term “antibody,” as used herein, also includes antigen-bindingfragments of full antibody molecules. The terms “antigen-bindingportion” of an antibody, “antigen-binding fragment” of an antibody, andthe like, as used herein, include any naturally occurring, enzymaticallyobtainable, synthetic, or genetically engineered polypeptide orglycoprotein that specifically binds an antigen to form a complex.Antigen-binding fragments of an antibody may be derived, e.g., from fullantibody molecules using any suitable standard techniques such asproteolytic digestion or recombinant genetic engineering techniquesinvolving the manipulation and expression of DNA encoding antibodyvariable and optionally constant domains. Such DNA is known and/or isreadily available from, e.g., commercial sources, DNA libraries(including, e.g., phage-antibody libraries), or can be synthesized. TheDNA may be sequenced and manipulated chemically or by using molecularbiology techniques, for example, to arrange one or more variable and/orconstant domains into a suitable configuration, or to introduce codons,create cysteine residues, modify, add or delete amino acids, etc.

Non-limiting examples of antigen-binding fragments include: (i) Fabfragments; (ii) F(ab')2 fragments; (iii) Fd fragments; (iv) Fvfragments; (v) single-chain Fv (scFv) molecules; (vi) dAb fragments; and(vii) minimal recognition units consisting of the amino acid residuesthat mimic the hypervariable region of an antibody (e.g., an isolatedcomplementarity determining region (CDR) such as a CDR3 peptide), or aconstrained FR3-CDR3-FR4 peptide. Other engineered molecules, such asdomain-specific antibodies, single domain antibodies, domain-deletedantibodies, chimeric antibodies, CDR-grafted antibodies, diabodies,triabodies, tetrabodies, minibodies, nanobodies (e.g. monovalentnanobodies, bivalent nanobodies, etc.), small modularimmunopharmaceuticals (SMIPs), and shark variable IgNAR domains, arealso encompassed within the expression “antigen-binding fragment,” asused herein.

An antigen-binding fragment of an antibody will typically comprise atleast one variable domain. The variable domain may be of any size oramino acid composition and will generally comprise at least one CDRwhich is adjacent to or in frame with one or more framework sequences.In antigen-binding fragments having a VH domain associated with a VLdomain, the VH and VL domains may be situated relative to one another inany suitable arrangement. For example, the variable region may bedimeric and contain VH-VH, VH-VL or VL-VL dimers. Alternatively, theantigen-binding fragment of an antibody may contain a monomeric VH or VLdomain.

In certain embodiments, an antigen-binding fragment of an antibody maycontain at least one variable domain covalently linked to at least oneconstant domain. Non-limiting, exemplary configurations of variable andconstant domains that may be found within an antigen-binding fragment ofan antibody of the present invention include: (i) VH-CH1; (ii) VH-CH2;(iii) VH-CH3; (iv) VH-CH1-CH2; (v) VH-CH1-CH2-CH3; (vi) VH-CH2-CH3;(vii) VH-CL; (viii) VL-CH1; (ix) VL-CH2; (x) VL-CH3; (xi) VL-CH1-CH2;(xii) VL-CH1-CH2-CH3; (xiii) VL-CH2-CH3; and (xiv) VL-CL. In anyconfiguration of variable and constant domains, including any of theexemplary configurations listed above, the variable and constant domainsmay be either directly linked to one another or may be linked by a fullor partial hinge or linker region. A hinge region may consist of atleast 2 (e.g., 5, 10, 15, 20, 40, 60 or more) amino acids which resultin a flexible or semi-flexible linkage between adjacent variable and/orconstant domains in a single polypeptide molecule. Moreover, anantigen-binding fragment of an antibody of the present invention maycomprise a homo-dimer or hetero-dimer (or other multimer) of any of thevariable and constant domain configurations listed above in non-covalentassociation with one another and/or with one or more monomeric VH or VLdomain (e.g., by disulfide bond(s)).

As with full antibody molecules, antigen-binding fragments may bemonospecific or multispecific (e.g., bispecific). A multispecificantigen-binding fragment of an antibody will typically comprise at leasttwo different variable domains, wherein each variable domain is capableof specifically binding to a separate antigen or to a different epitopeon the same antigen. Any multispecific antibody format, including theexemplary bispecific antibody formats disclosed herein, may be adaptedfor use in the context of an antigen-binding fragment of an antibody ofthe present invention using routine techniques available in the art.

The constant region of an antibody is important in the ability of anantibody to fix complement and mediate cell-dependent cytotoxicity.Thus, the isotype of an antibody may be selected on the basis of whetherit is desirable for the antibody to mediate cytotoxicity.

The term “human antibody”, as used herein, is intended to includeantibodies having variable and constant regions derived from humangermline immunoglobulin sequences. The human antibodies of the inventionmay nonetheless include amino acid residues not encoded by humangermline immunoglobulin sequences (e.g., mutations introduced by randomor site-specific mutagenesis in vitro or by somatic mutation in vivo),for example in the CDRs and in particular CDR3. However, the term “humanantibody”, as used herein, is not intended to include antibodies inwhich CDR sequences derived from the germline of another mammalianspecies, such as a mouse, have been grafted onto human frameworksequences.

The term “recombinant human antibody”, as used herein, is intended toinclude all human antibodies that are prepared, expressed, created orisolated by recombinant means, such as antibodies expressed using arecombinant expression vector transfected into a host cell (describedfurther below), antibodies isolated from a recombinant, combinatorialhuman antibody library (described further below), antibodies isolatedfrom an animal (e.g., a mouse) that is transgenic for humanimmunoglobulin genes (see e.g., Taylor et al. (1992) Nucl. Acids Res.20:6287-6295) or antibodies prepared, expressed, created or isolated byany other means that involves splicing of human immunoglobulin genesequences to other DNA sequences. Such recombinant human antibodies havevariable and constant regions derived from human germline immunoglobulinsequences. In certain embodiments, however, such recombinant humanantibodies are subjected to in vitro mutagenesis (or, when an animaltransgenic for human Ig sequences is used, in vivo somatic mutagenesis)and thus the amino acid sequences of the VH and VL regions of therecombinant antibodies are sequences that, while derived from andrelated to human germline VH and VL sequences, may not naturally existwithin the human antibody germline repertoire in vivo.

Human antibodies can exist in two forms that are associated with hingeheterogeneity. In one form, an immunoglobulin molecule comprises astable four chain construct of approximately 150-160 kDa in which thedimers are held together by an interchain heavy chain disulfide bond. Ina second form, the dimers are not linked via inter-chain disulfide bondsand a molecule of about 75-80 kDa is formed composed of a covalentlycoupled light and heavy chain (half-antibody). These forms have beenextremely difficult to separate, even after affinity purification.

The frequency of appearance of the second form in various intact IgGisotypes is due to, but not limited to, structural differencesassociated with the hinge region isotype of the antibody. A single aminoacid substitution in the hinge region of the human IgG4 hinge cansignificantly reduce the appearance of the second form (Angal et al.(1993) Molecular Immunology 30:105) to levels typically observed using ahuman IgG1 hinge. The instant invention encompasses antibodies havingone or more mutations in the hinge, CH2 or CH3 region which may bedesirable, for example, in production, to improve the yield of thedesired antibody form.

An “isolated antibody,” as used herein, means an antibody that has beenidentified and separated and/or recovered from at least one component ofits natural environment. For example, an antibody that has beenseparated or removed from at least one component of an organism, or froma tissue or cell in which the antibody naturally exists or is naturallyproduced, is an “isolated antibody” for purposes of the presentinvention. An isolated antibody also includes an antibody in situ withina recombinant cell. Isolated antibodies are antibodies that have beensubjected to at least one purification or isolation step. According tocertain embodiments, an isolated antibody may be substantially free ofother cellular material and/or chemicals.

The term “specifically binds,” or the like, means that an antibody orantigen-binding fragment thereof forms a complex with an antigen that isrelatively stable under physiologic conditions. Methods for determiningwhether an antibody specifically binds to an antigen are well known inthe art and include, for example, equilibrium dialysis, surface plasmonresonance, and the like. For example, an antibody that “specificallybinds” PCSK9, as used in the context of the present invention, includesantibodies that bind PCSK9 or portion thereof with a KD of less thanabout 1000 nM, less than about 500 nM, less than about 300 nM, less thanabout 200 nM, less than about 100 nM, less than about 90 nM, less thanabout 80 nM, less than about 70 nM, less than about 60 nM, less thanabout 50 nM, less than about 40 nM, less than about 30 nM, less thanabout 20 nM, less than about 10 nM, less than about 5 nM, less thanabout 4 nM, less than about 3 nM, less than about 2 nM, less than about1 nM or less than about 0.5 nM, as measured in a surface plasmonresonance assay. An isolated antibody that specifically binds humanPCSK9, however, have cross-reactivity to other antigens, such as PCSK9molecules from other (non-human) species.

The anti-PCSK9 antibodies useful for the methods of the presentinvention may comprise one or more amino acid substitutions, insertionsand/or deletions in the framework and/or CDR regions of the heavy andlight chain variable domains as compared to the corresponding germlinesequences from which the antibodies were derived. Such mutations can bereadily ascertained by comparing the amino acid sequences disclosedherein to germline sequences available from, for example, publicantibody sequence databases. The present invention includes methodsinvolving the use of antibodies, and antigen-binding fragments thereof,which are derived from any of the amino acid sequences disclosed herein,wherein one or more amino acids within one or more framework and/or CDRregions are mutated to the corresponding residue(s) of the germlinesequence from which the antibody was derived, or to the correspondingresidue(s) of another human germline sequence, or to a conservativeamino acid substitution of the corresponding germline residue(s) (suchsequence changes are referred to herein collectively as “germlinemutations”). A person of ordinary skill in the art, starting with theheavy and light chain variable region sequences disclosed herein, caneasily produce numerous antibodies and antigen-binding fragments whichcomprise one or more individual germline mutations or combinationsthereof. In certain embodiments, all of the framework and/or CDRresidues within the VH and/or VL domains are mutated back to theresidues found in the original germline sequence from which the antibodywas derived. In other embodiments, only certain residues are mutatedback to the original germline sequence, e.g., only the mutated residuesfound within the first 8 amino acids of FR1 or within the last 8 aminoacids of FR4, or only the mutated residues found within CDR1, CDR2 orCDR3. In other embodiments, one or more of the framework and/or CDRresidue(s) are mutated to the corresponding residue(s) of a differentgermline sequence (i.e., a germline sequence that is different from thegermline sequence from which the antibody was originally derived).Furthermore, the antibodies of the present invention may contain anycombination of two or more germline mutations within the frameworkand/or CDR regions, e.g., wherein certain individual residues aremutated to the corresponding residue of a particular germline sequencewhile certain other residues that differ from the original germlinesequence are maintained or are mutated to the corresponding residue of adifferent germline sequence. Once obtained, antibodies andantigen-binding fragments that contain one or more germline mutationscan be easily tested for one or more desired property such as, improvedbinding specificity, increased binding affinity, improved or enhancedantagonistic or agonistic biological properties (as the case may be),reduced immunogenicity, etc. The use of antibodies and antigen-bindingfragments obtained in this general manner are encompassed within thepresent invention.

The present invention also includes methods involving the use ofanti-PCSK9 antibodies comprising variants of any of the HCVR, LCVR,and/or CDR amino acid sequences disclosed herein having one or moreconservative substitutions. For example, the present invention includesthe use of anti-PCSK9 antibodies having HCVR, LCVR, and/or CDR aminoacid sequences with, e.g., 10 or fewer, 8 or fewer, 6 or fewer, 4 orfewer, etc. conservative amino acid substitutions relative to any of theHCVR, LCVR, and/or CDR amino acid sequences disclosed herein.

The term “surface plasmon resonance”, as used herein, refers to anoptical phenomenon that allows for the analysis of real-timeinteractions by detection of alterations in protein concentrationswithin a biosensor matrix, for example using the BIAcore™ system(Biacore Life Sciences division of GE Healthcare, Piscataway, N.J.).

The term “KD”, as used herein, is intended to refer to the equilibriumdissociation constant of a particular antibody-antigen interaction.

The term “epitope” refers to an antigenic determinant that interactswith a specific antigen binding site in the variable region of anantibody molecule known as a paratope. A single antigen may have morethan one epitope. Thus, different antibodies may bind to different areason an antigen and may have different biological effects. Epitopes may beeither conformational or linear. A conformational epitope is produced byspatially juxtaposed amino acids from different segments of the linearpolypeptide chain. A linear epitope is one produced by adjacent aminoacid residues in a polypeptide chain. In certain circumstances, anepitope may include moieties of saccharides, phosphoryl groups, orsulfonyl groups on the antigen.

According to certain embodiments, the anti-PCSK9 antibody used in themethods of the present invention is an antibody with pH-dependentbinding characteristics. As used herein, the expression “pH-dependentbinding” means that the antibody or antigen-binding fragment thereofexhibits “reduced binding to PCSK9 at acidic pH as compared to neutralpH” (for purposes of the present disclosure, both expressions may beused interchangeably). For example, antibodies “with pH-dependentbinding characteristics” includes antibodies and antigen-bindingfragments thereof that bind PCSK9 with higher affinity at neutral pHthan at acidic pH. In certain embodiments, the antibodies andantigen-binding fragments of the present invention bind PCSK9 with atleast 3, 5, 10, 15, 20, 25, 30, 35, 40, 45, 50, 55, 60, 65, 70, 75, 80,85, 90, 95, 100, or more times higher affinity at neutral pH than atacidic pH.

According to this aspect of the invention, the anti-PCSK9 antibodieswith pH-dependent binding characteristics may possess one or more aminoacid variations relative to the parental anti-PCSK9 antibody. Forexample, an anti-PCSK9 antibody with pH-dependent bindingcharacteristics may contain one or more histidine substitutions orinsertions, e.g., in one or more CDRs of a parental anti-PCSK9 antibody.Thus, according to certain embodiments of the present invention, methodsare provided comprising administering an anti-PCSK9 antibody whichcomprises CDR amino acid sequences (e.g., heavy and light chain CDRs)which are identical to the CDR amino acid sequences of a parentalanti-PCSK9 antibody, except for the substitution of one or more aminoacids of one or more CDRs of the parental antibody with a histidineresidue. The anti-PCSK9 antibodies with pH-dependent binding maypossess, e.g., 1, 2, 3, 4, 5, 6, 7, 8, 9, or more histidinesubstitutions, either within a single CDR of a parental antibody ordistributed throughout multiple (e.g., 2, 3, 4, 5, or 6) CDRs of aparental anti-PCSK9 antibody. For example, the present inventionincludes the use of anti-PCSK9 antibodies with pH-dependent bindingcomprising one or more histidine substitutions in HCDR1, one or morehistidine substitutions in HCDR2, one or more histidine substitutions inHCDR3, one or more histidine substitutions in LCDR1, one or morehistidine substitutions in LCDR2, and/or one or more histidinesubstitutions in LCDR3, of a parental anti-PCSK9 antibody.

As used herein, the expression “acidic pH” means a pH of 6.0 or less(e.g., less than about 6.0, less than about 5.5, less than about 5.0,etc.). The expression “acidic pH” includes pH values of about 6.0, 5.95,5.90, 5.85, 5.8, 5.75, 5.7, 5.65, 5.6, 5.55, 5.5, 5.45, 5.4, 5.35, 5.3,5.25, 5.2, 5.15, 5.1, 5.05, 5.0, or less. As used herein, the expression“neutral pH” means a pH of about 7.0 to about 7.4. The expression“neutral pH” includes pH values of about 7.0, 7.05, 7.1, 7.15, 7.2,7.25, 7.3, 7.35, and 7.4.

Preparation of Human Antibodies

Methods for generating human antibodies in transgenic mice are known inthe art. Any such known methods can be used in the context of thepresent invention to make human antibodies that specifically bind tohuman PCSK9.

Using VELOCIMMUNE® technology (see, for example, U.S. Pat. No.6,596,541, Regeneron Pharmaceuticals) or any other known method forgenerating monoclonal antibodies, high affinity chimeric antibodies toPCSK9 are initially isolated having a human variable region and a mouseconstant region. The VELOCIMMUNE® technology involves generation of atransgenic mouse having a genome comprising human heavy and light chainvariable regions operably linked to endogenous mouse constant regionloci such that the mouse produces an antibody comprising a humanvariable region and a mouse constant region in response to antigenicstimulation. The DNA encoding the variable regions of the heavy andlight chains of the antibody are isolated and operably linked to DNAencoding the human heavy and light chain constant regions. The DNA isthen expressed in a cell capable of expressing the fully human antibody.

Generally, a VELOCIMMUNE® mouse is challenged with the antigen ofinterest, and lymphatic cells (such as B-cells) are recovered from themice that express antibodies. The lymphatic cells may be fused with amyeloma cell line to prepare immortal hybridoma cell lines, and suchhybridoma cell lines are screened and selected to identify hybridomacell lines that produce antibodies specific to the antigen of interest.DNA encoding the variable regions of the heavy chain and light chain maybe isolated and linked to desirable isotypic constant regions of theheavy chain and light chain. Such an antibody protein may be produced ina cell, such as a CHO cell. Alternatively, DNA encoding theantigen-specific chimeric antibodies or the variable domains of thelight and heavy chains may be isolated directly from antigen-specificlymphocytes.

Initially, high affinity chimeric antibodies are isolated having a humanvariable region and a mouse constant region. The antibodies arecharacterized and selected for desirable characteristics, includingaffinity, selectivity, epitope, etc, using standard procedures known tothose skilled in the art. The mouse constant regions are replaced with adesired human constant region to generate the fully human antibody ofthe invention, for example wild-type or modified IgG1 or IgG4. While theconstant region selected may vary according to specific use, highaffinity antigen-binding and target specificity characteristics residein the variable region.

In general, the antibodies that can be used in the methods of thepresent invention possess high affinities, as described above, whenmeasured by binding to antigen either immobilized on solid phase or insolution phase. The mouse constant regions are replaced with desiredhuman constant regions to generate the fully human antibodies of theinvention. While the constant region selected may vary according tospecific use, high affinity antigen-binding and target specificitycharacteristics reside in the variable region.

Specific examples of human antibodies or antigen-binding fragments ofantibodies that specifically bind PCSK9 which can be used in the contextof the methods of the present invention include any antibody orantigen-binding fragment which comprises the three heavy chain CDRs(HCDR1, HCDR2 and HCDR3) contained within a heavy chain variable region(HCVR) having an amino acid sequence selected from the group consistingof SEQ ID NOs: 1 and 11, or a substantially similar sequence thereofhaving at least 90%, at least 95%, at least 98% or at least 99% sequenceidentity. Alternatively, specific examples of human antibodies orantigen-binding fragments of antibodies that specifically bind PCSK9which can be used in the context of the methods of the present inventioninclude any antibody or antigen-binding fragment which comprises thethree heavy chain CDRs (HCDR1, HCDR2 and HCDR3) contained within a heavychain variable region (HCVR) having an amino acid sequence selected fromthe group consisting of SEQ ID NOs 37, 45, 53, 61, 69, 77, 85, 93, 101,109, 117, 125, 133, 141, 149, 157, 165, 173, 181, and 189, orasubstantially similar sequence thereof having at least 90%, at least95%, at least 98% or at least 99% sequence identity. The antibody orantigen-binding fragment may comprise the three light chain CDRs (LCVR1,LCVR2, LCVR3) contained within a light chain variable region (LCVR)having an amino acid sequence selected from the group consisting of SEQID NOs: 6 and 15, or a substantially similar sequence thereof having atleast 90%, at least 95%, at least 98% or at least 99% sequence identity.Alternatively, the antibody or antigen-binding fragment may comprise thethree light chain CDRs (LCVR1, LCVR2, LCVR3) contained within a lightchain variable region (LCVR) having an amino acid sequence selected fromthe group consisting of SEQ ID NOs 41, 49, 57, 65, 73, 81, 89, 97, 105,113, 121, 129, 137, 145, 153, 161, 169, 177, 185, and 193, orasubstantially similar sequence thereof having at least 90%, at least95%, at least 98% or at least 99% sequence identity.

In certain embodiments of the present invention, the antibody orantigen-binding fragment thereof comprises the six CDRs (HCDR1, HCDR2,HCDR3, LCDR1, LCDR2 and LCDR3) from the heavy and light chain variableregion amino acid sequence pairs (HCVR/LCVR) selected from the groupconsisting of SEQ ID NOs:1/6 and 11/15. Alternatively, in certainembodiments of the present invention, the antibody or antigen-bindingprotein comprises the six CDRs (HCDR1, HCDR2, HCDR3, LCDR1, LCDR2 andLCDR3) from the heavy and light chain variable region amino acidsequence pairs (HCVR/LCVR) selected from the group consisting of SEQ IDNOs:37/41, 45/49, 53/57, 61/65, 69/73, 77/81, 85/89, 93/97, 101/105,109/113, 117/121, 125/129, 133/137, 141/145, 149/153, 157/161, 165/169,173/177, 181/185, and 189/193.

In certain embodiments of the present invention, the anti-PCSK9antibody, or antigen-binding fragment thereof, that can be used in themethods of the present invention has HCDR1/HCDR2/HCDR3/LCDR1/LCDR2/LCDR3amino acid sequences selected from SEQ ID NOs: 2/3/4/7/8/10 (mAb316P)and 12/13/14/16/17/18 (mAb300N) (See US Patent App. Publ No.2010/0166768).

In certain embodiments of the present invention, the antibody orantigen-binding fragment thereof comprises HCVR/LCVR amino acid sequencepairs selected from the group consisting of SEQ ID NOs: 1/6 and 11/15.Alternatively, in certain embodiments of the present invention, theantibody or antigen-binding protein comprises HCVR/LCVR amino acidsequence pairs selected from the group consisting of SEQ ID NOs:37/41,45/49, 53/57, 61/65, 69/73, 77/81, 85/89, 93/97, 101/105, 109/113,117/121, 125/129, 133/137, 141/145, 149/153, 157/161, 165/169, 173/177,181/185, and 189/193.

Pharmaceutical Compositions and Methods of Administration

The present invention includes methods which comprise administering aPCSK9 inhibitor to a patient with heterozygous familialhypercholesterolemia who is not adequately controlled by maximumtolerated dose statin therapy with or without other lipid loweringtherapy, wherein the PCSK9 inhibitor is contained within apharmaceutical composition. The pharmaceutical compositions of theinvention are formulated with suitable carriers, excipients, and otheragents that provide suitable transfer, delivery, tolerance, and thelike. A multitude of appropriate formulations can be found in theformulary known to all pharmaceutical chemists: Remington'sPharmaceutical Sciences, Mack Publishing Company, Easton, Pa. Theseformulations include, for example, powders, pastes, ointments, jellies,waxes, oils, lipids, lipid (cationic or anionic) containing vesicles(such as LIPOFECTIN™), DNA conjugates, anhydrous absorption pastes,oil-in-water and water-in-oil emulsions, emulsions carbowax(polyethylene glycols of various molecular weights), semi-solid gels,and semi-solid mixtures containing carbowax. See also Powell et al.“Compendium of excipients for parenteral formulations” PDA (1998) JPharm Sci Technol 52:238-311.

Various delivery systems are known and can be used to administer thepharmaceutical composition of the invention, e.g., encapsulation inliposomes, microparticles, microcapsules, recombinant cells capable ofexpressing the mutant viruses, receptor mediated endocytosis (see, e.g.,Wu et al., 1987, J. Biol. Chem. 262:4429-4432). Methods ofadministration include, but are not limited to, intradermal,intramuscular, intraperitoneal, intravenous, subcutaneous, intranasal,epidural, and oral routes. The composition may be administered by anyconvenient route, for example by infusion or bolus injection, byabsorption through epithelial or mucocutaneous linings (e.g., oralmucosa, rectal and intestinal mucosa, etc.) and may be administeredtogether with other biologically active agents.

A pharmaceutical composition of the present invention can be deliveredsubcutaneously or intravenously with a standard needle and syringe. Inaddition, with respect to subcutaneous delivery, a pen delivery devicereadily has applications in delivering a pharmaceutical composition ofthe present invention. Such a pen delivery device can be reusable ordisposable. A reusable pen delivery device generally utilizes areplaceable cartridge that contains a pharmaceutical composition. Onceall of the pharmaceutical composition within the cartridge has beenadministered and the cartridge is empty, the empty cartridge can readilybe discarded and replaced with a new cartridge that contains thepharmaceutical composition. The pen delivery device can then be reused.In a disposable pen delivery device, there is no replaceable cartridge.Rather, the disposable pen delivery device comes prefilled with thepharmaceutical composition held in a reservoir within the device. Oncethe reservoir is emptied of the pharmaceutical composition, the entiredevice is discarded.

Numerous reusable pen and autoinjector delivery devices haveapplications in the subcutaneous delivery of a pharmaceuticalcomposition of the present invention. Examples include, but are notlimited to AUTOPEN™ (Owen Mumford, Inc., Woodstock, UK), DISETRONIC™ pen(Disetronic Medical Systems, Bergdorf, Switzerland), HUMALOG MIX 75/25™pen, HUMALOG™ pen, HUMALIN 70/30™ pen (Eli Lilly and Co., Indianapolis,Ind.), NOVOPEN™ I, II and III (Novo Nordisk, Copenhagen, Denmark),NOVOPEN JUNIOR™ (Novo Nordisk, Copenhagen, Denmark), BD™ pen (BectonDickinson, Franklin Lakes, N.J.), OPTIPEN™, OPTIPEN PRO™, OPTIPENSTARLET™, and OPTICLIK™ (sanofi-aventis, Frankfurt, Germany), to nameonly a few. Examples of disposable pen delivery devices havingapplications in subcutaneous delivery of a pharmaceutical composition ofthe present invention include, but are not limited to the SOLOSTAR™ pen(sanofi-aventis), the FLEXPEN™ (Novo Nordisk), and the KWIKPEN™ (EliLilly), the SURECLICK™ Autoinjector (Amgen, Thousand Oaks, Calif.), thePENLET™ (Haselmeier, Stuttgart, Germany), the EPIPEN (Dey, L.P.), andthe HUMIRA™ Pen (Abbott Labs, Abbott Park Ill.), to name only a few.

In certain situations, the pharmaceutical composition can be deliveredin a controlled release system. In one embodiment, a pump may be used(see Langer, supra; Sefton, 1987, CRC Crit. Ref. Biomed. Eng. 14:201).In another embodiment, polymeric materials can be used; see, MedicalApplications of Controlled Release, Langer and Wise (eds.), 1974, CRCPres., Boca Raton, Fla. In yet another embodiment, a controlled releasesystem can be placed in proximity of the composition's target, thusrequiring only a fraction of the systemic dose (see, e.g., Goodson,1984, in Medical Applications of Controlled Release, supra, vol. 2, pp.115-138). Other controlled release systems are discussed in the reviewby Langer, 1990, Science 249:1527-1533.

The injectable preparations may include dosage forms for intravenous,subcutaneous, intracutaneous and intramuscular injections, dripinfusions, etc. These injectable preparations may be prepared by knownmethods. For example, the injectable preparations may be prepared, e.g.,by dissolving, suspending or emulsifying the antibody or its saltdescribed above in a sterile aqueous medium or an oily mediumconventionally used for injections. As the aqueous medium forinjections, there are, for example, physiological saline, an isotonicsolution containing glucose and other auxiliary agents, etc., which maybe used in combination with an appropriate solubilizing agent such as analcohol (e.g., ethanol), a polyalcohol (e.g., propylene glycol,polyethylene glycol), a nonionic surfactant [e.g., polysorbate 80,HCO-50 (polyoxyethylene (50 mol) adduct of hydrogenated castor oil)],etc. As the oily medium, there are employed, e.g., sesame oil, soybeanoil, etc., which may be used in combination with a solubilizing agentsuch as benzyl benzoate, benzyl alcohol, etc. The injection thusprepared is preferably filled in an appropriate ampoule.

Advantageously, the pharmaceutical compositions for oral or parenteraluse described above are prepared into dosage forms in a unit dose suitedto fit a dose of the active ingredients. Such dosage forms in a unitdose include, for example, tablets, pills, capsules, injections(ampoules), suppositories, etc.

Dosage

The amount of PCSK9 inhibitor (e.g., anti-PCSK9 antibody) administeredto a patient with heterozygous familial hypercholesterolemia who is notadequately controlled by maximum tolerated dose statin therapy with orwithout other lipid lowering therapy according to the methods of thepresent invention is, generally, a therapeutically effective amount. Asused herein, the phrase “therapeutically effective amount” means a doseof PCSK9 inhibitor that results in a detectable improvement (at leastabout 5%, 10%, 15%, 20%, 25%, 30%, 35%, 40%, 45%, 50%, 55%, 60%, 65%,70%, 75%, or more from baseline) in one or more parameters selected fromthe group consisting of LDL-C, ApoB, non-HDL-C, total cholesterol,HLDL-C, triglycerides, Apo A-1, and Lp(a).

In the case of an anti-PCSK9 antibody, a therapeutically effectiveamount can be from about 0.05 mg to about 600 mg, e.g., about 0.05 mg,about 0.1 mg, about 1.0 mg, about 1.5 mg, about 2.0 mg, about 10 mg,about 20 mg, about 30 mg, about 40 mg, about 50 mg, about 60 mg, about70 mg, about 75 mg, about 80 mg, about 90 mg, about 100 mg, about 110mg, about 120 mg, about 130 mg, about 140 mg, about 150 mg, about 160mg, about 170 mg, about 180 mg, about 190 mg, about 200 mg, about 210mg, about 220 mg, about 230 mg, about 240 mg, about 250 mg, about 260mg, about 270 mg, about 280 mg, about 290 mg, about 300 mg, about 310mg, about 320 mg, about 330 mg, about 340 mg, about 350 mg, about 360mg, about 370 mg, about 380 mg, about 390 mg, about 400 mg, about 410mg, about 420 mg, about 430 mg, about 440 mg, about 450 mg, about 460mg, about 470 mg, about 480 mg, about 490 mg, about 500 mg, about 510mg, about 520 mg, about 530 mg, about 540 mg, about 550 mg, about 560mg, about 570 mg, about 580 mg, about 590 mg, or about 600 mg, of theanti-PCSK9 antibody.

The amount of anti-PCSK9 antibody contained within the individual dosesmay be expressed in terms of milligrams of antibody per kilogram ofpatient body weight (i.e., mg/kg). For example, the anti-PCSK9 antibodymay be administered to a patient at a dose of about 0.0001 to about 10mg/kg of patient body weight.

Combination Therapies

As described elsewhere herein, the methods of the present invention maycomprise administering a PCSK9 inhibitor to patients with heterozygousfamilial hypercholesterolemia in combination with the patient'spreviously prescribed stable daily maximum tolerated dose therapeuticstatin regimen. According to certain embodiments of the presentinvention, additional therapeutic agents, besides a statin, may beadministered to the patient in combination with the PCSK9 inhibitor.Examples of such additional therapeutic agents include e.g., (1) anagent which inhibits cholesterol uptake and or bile acid re-absorption(e.g., ezetimibe); (2) an agent which increases lipoprotein catabolism(such as niacin); and/or (3) activators of the LXR transcription factorthat plays a role in cholesterol elimination such as22-hydroxycholesterol.

Administration Regimens

According to certain embodiments of the present invention, multipledoses of a PCSK9 inhibitor (i.e., a pharmaceutical compositioncomprising a PCSK9 inhibitor) may be administered to a subject over adefined time course (e.g., on top of a daily therapeutic statinregimen). The methods according to this aspect of the invention comprisesequentially administering to a patient with heterozygous familialhypercholesterolemia who is not adequately controlled by maximumtolerated dose statin therapy with or without other lipid loweringtherapy multiple doses of a PCSK9 inhibitor. As used herein,“sequentially administering” means that each dose of PCSK9 inhibitor isadministered to the subject at a different point in time, e.g., ondifferent days separated by a predetermined interval (e.g., hours, days,weeks or months). The present invention includes methods which comprisesequentially administering to the patient with heterozygous familialhypercholesterolemia a single initial dose of a PCSK9 inhibitor,followed by one or more secondary doses of the PCSK9 inhibitor, andoptionally followed by one or more tertiary doses of the PCSK9inhibitor.

The terms “initial dose,” “secondary doses,” and “tertiary doses,” referto the temporal sequence of administration of the individual doses of apharmaceutical composition comprising a PCSK9 inhibitor. Thus, the“initial dose” is the dose which is administered at the beginning of thetreatment regimen (also referred to as the “baseline dose”); the“secondary doses” are the doses which are administered after the initialdose; and the “tertiary doses” are the doses which are administeredafter the secondary doses. The initial, secondary, and tertiary dosesmay all contain the same amount of the PCSK9 inhibitor, but generallymay differ from one another in terms of frequency of administration. Incertain embodiments, however, the amount of PCSK9 inhibitor contained inthe initial, secondary and/or tertiary doses varies from one another(e.g., adjusted up or down as appropriate) during the course oftreatment. In certain embodiments, two or more (e.g., 2, 3, 4, or 5)doses are administered at the beginning of the treatment regimen as“loading doses” followed by subsequent doses that are administered on aless frequent basis (e.g., “maintenance doses”).

According to exemplary embodiments of the present invention, eachsecondary and/or tertiary dose is administered 1 to 26 (e.g., 1, 1½, 2,2½, 3, 3½, 4, 4½, 5, 5½, 6, 6½, 7, 7½, 8, 8½, 9, 9½, 10, 10½, 11, 11½,12, 12½, 13, 13½, 14, 14½, 15, 15½, 16, 16½, 17, 17½, 18, 18½, 19, 19½,20, 20½, 21, 21½, 22, 22½, 23, 23½, 24, 24½, 25, 25½, 26, 26½, or more)weeks after the immediately preceding dose. The phrase “the immediatelypreceding dose,” as used herein, means, in a sequence of multipleadministrations, the dose of antigen-binding molecule which isadministered to a patient prior to the administration of the very nextdose in the sequence with no intervening doses.

The methods according to this aspect of the invention may compriseadministering to a patient with heterozygous familialhypercholesterolemia any number of secondary and/or tertiary doses of aPCSK9 inhibitor. For example, in certain embodiments, only a singlesecondary dose is administered to the patient. In other embodiments, twoor more (e.g., 2, 3, 4, 5, 6, 7, 8, or more) secondary doses areadministered to the patient. Likewise, in certain embodiments, only asingle tertiary dose is administered to the patient. In otherembodiments, two or more (e.g., 2, 3, 4, 5, 6, 7, 8, or more) tertiarydoses are administered to the patient.

In embodiments involving multiple secondary doses, each secondary dosemay be administered at the same frequency as the other secondary doses.For example, each secondary dose may be administered to the patient withheterozygous familial hypercholesterolemia 1 to 2, 4, 6, 8 or more weeksafter the immediately preceding dose. Similarly, in embodimentsinvolving multiple tertiary doses, each tertiary dose may beadministered at the same frequency as the other tertiary doses. Forexample, each tertiary dose may be administered to the patient 1 to 2,4, 6, 8 or more weeks after the immediately preceding dose.Alternatively, the frequency at which the secondary and/or tertiarydoses are administered to a patient can vary over the course of thetreatment regimen. The frequency of administration may also be adjustedduring the course of treatment by a physician depending on the needs ofthe individual patient following clinical examination.

The present invention includes administration regimens comprising anup-titration option (also referred to herein as “dose modification”). Asused herein, an “up-titration option” means that, after receiving aparticular number of doses of a PCSK9 inhibitor, if a patient has notachieved a specified reduction in one or more defined therapeuticparameters, the dose of the PCSK9 inhibitor is thereafter increased. Forexample, in the case of a therapeutic regimen comprising administrationof 75 mg doses of an anti-PCSK9 antibody to a patient with heterozygousfamilial hypercholesterolemia who is not adequately controlled bymaximum tolerated dose statin therapy with or without other lipidlowering therapy at a frequency of once every two weeks, if after 8weeks (i.e., 5 doses administered at Week 0, Week 2 and Week 4, Week 6and Week 8), the patient has not achieved a serum LDL-C concentration ofless than 70 mg/dL, then the dose of anti-PCSK9 antibody is increased toe.g., 150 mg administered once every two weeks thereafter (e.g.,starting at Week 12).

In certain embodiments, the anti-PCSK9 antibody is administered to asubject at a dose of about 75 mg every two weeks, for example for atleast six doses.

In some embodiments, the antibody is administered to a subject at a doseof about 75 mg every two weeks for 12 weeks, and the dose remains at 75mg every two weeks if, at week 8, the subject's LDL-C value was lessthan 70 mg/dl.

In other embodiments, the antibody is administered to a subject at adose of about 75 mg every two weeks for 12 weeks, and the dose istitrated up to about 150 mg every two weeks if, at week 8, the subject'sLDL-C value was greater than or equal to 70 mg/dl. In certainembodiments, the anti-PCSK9 antibody is administered to a subject at adose of about 150 mg every two weeks, for example for at least sixdoses.

EXAMPLES

The following examples are put forth so as to provide those of ordinaryskill in the art with a complete disclosure and description of how tomake and use the methods and compositions of the invention, and are notintended to limit the scope of what the inventors regard as theirinvention. Efforts have been made to ensure accuracy with respect tonumbers used (e.g., amounts, temperature, etc.) but some experimentalerrors and deviations should be accounted for. Unless indicatedotherwise, parts are parts by weight, molecular weight is averagemolecular weight, temperature is in degrees Centigrade, and pressure isat or near atmospheric.

Example 1 Generation of Human Antibodies to Human PCSK9

Human anti-PCSK9 antibodies were generated as described in U.S. Pat. No.8,062,640. The exemplary PCSK9 inhibitor used in the following Examplesis the human anti-PCSK9 antibody designated “mAb316P,” also known as“Alirocumab.” mAb316P has the following amino acid sequencecharacteristics: heavy chain variable region (HCVR) comprising SEQ IDNO:1; light chain variable domain (LCVR) comprising SEQ ID NO:6; heavychain complementarity determining region 1 (HCDR1) comprising SEQ IDNO:2; HCDR2 comprising SEQ ID NO:3; HCDR3 comprising SEQ ID NO:4; lightchain complementarity determining region 1 (LCDR1) comprising SEQ IDNO:7; LCDR2 comprising SEQ ID NO:8; and LCDR3 comprising SEQ ID NO:10.

Example 2 A Randomized, Double-Blind, Placebo-Controlled, Parallel GroupStudy to Evaluate the Efficacy and Safety of Alirocumab in Patients WithHeterozygous Familial Hypercholesterolemia Not Adequately ControlledWith Their Lipid-Modifying Therapy Introduction

This study included patients with heterozygous familialhypercholesterolemia (heFH) with or without a history of documentedmyocardial infarction (MI) or ischemic stroke.

The objective of the study was to assess the efficacy and safety ofAlirocumab in patients with heFH and who require additionalpharmacological management since their current lipid-modifying therapy(LMT) failed to achieve the LDL-C treatment goal.

This study (FIG. 1) was undertaken to demonstrate in heFH patients whoare not at their LDL-C goal that Alirocumab 75 mg Q2W or 75 mg Q2W/150mg Q2W as add-on therapy to statin±other LMT causes a statisticallysignificant and clinically meaningful reduction in LDL-C. Thispopulation that is not at LDL-C goal on optimized LMT represents thehighest risk group with a well identified unmet medical need that can beaddressed by adding Alirocumab to their LDL-C lowering therapies.

Study Objectives

The primary objective of the study was to demonstrate the reduction ofLDL-C by Alirocumab as add-on therapy to stable maximally tolerateddaily statin therapy with or without other LMT in comparison withplacebo after 24 weeks of treatment in patients with heFH.

The secondary objectives of the study were: 1) to evaluate the effect ofAlirocumab 75 mg in comparison with placebo on LDL-C after 12 weeks oftreatment; 2) to evaluate the effect of Alirocumab on other lipidparameters (i.e., Apo B, non-HDL-C, total-C, Lp (a), HDL-C, TG levels,and Apo A-1 levels); 3) to evaluate the long-term effect of Alirocumabon LDL-C; 4) to evaluate the safety and tolerability of Alirocumab; 5)to evaluate the development of anti-Alirocumab antibodies; and 6) toevaluate the PK of Alirocumab.

Study Design

This was a randomized, double-blind, placebo-controlled, parallel-group,unbalanced (2:1, Alirocumab:placebo), multi-center, multi-national studyto assess the efficacy and the safety of Alirocumab in patients withheFH not adequately controlled with their LMT (i.e., stable maximallytolerated daily statin therapy±other LMT). Not adequately controlled wasdefined as an LDL-C≥70 mg/dL (1.81 mmol/L) at the screening visit(Week-3) in patients with a history of documented cardiovascular diseaseor LDL-C≥100 mg/dL (2.59 mmol/L) at the screening visit (Week-3) inpatients without a history of documented cardiovascular disease.Randomization was stratified according to prior history of MI orischemic stroke [Yes/No], statin treatment (atorvastatin 40 to 80 mgdaily or rosuvastatin 20 to 40 mg daily vs. simvastatin whatever thedaily dose, atorvastatin below 40 mg daily or rosuvastatin below 20 mgdaily) and geographic region. After randomization, patients receiveddouble-blind study treatment (either Alirocumab or placebo) Q2W over aperiod of 18 months (78 weeks) on top of stable maximally tolerateddaily statin therapy±other LMT. A dose up-titration depending on Week 8LDL-C levels may occur at Week 12 for patients randomized to Alirocumab.After completion of the 18-month double-blind treatment period, allpatients who successfully completed the study had the opportunity toparticipate in an open-label extension study. Consequently all patientsreceived Alirocumab at entry in the open-label extension studyregardless of the study treatment they received during the 18-monthdouble-blind treatment period.

The study consisted of 3 periods: screening, double-blind treatment, andfollow-up.

The screening period was up to 3 weeks in duration including anintermediate visit during which the patient (or another designatedperson such as spouse, relative, etc.) was trained to self-inject/injectwith placebo for Alirocumab. Eligibility assessments were performed topermit the randomization of patients into the study.

The double blind treatment period (DBTP) was a randomized, double-blindstudy treatment period of 18 months. The first injection during thedouble-blind period was done at the site on the day of randomization(Week 0 [D1]-V3). The subsequent injections were done by the patient(self-injection) or another designated person (such as spouse, relative,etc.) at a patient-preferred location (home . . . ). Patients randomizedto Alirocumab received a dose of 75 mg of the Investigational MedicinalProduct (IMP) from randomization (V3) up to Week 12 (V6) (i.e., Weeks 0,2, 4, 6, 8, and 10). At the Week 12 visit (V6) these patients, in ablinded manner, either: 1) continued Alirocumab 75 mg Q2W from Week 12onwards until the last injection at Week 76, if the Week 8 LDL-C was <70mg/dL (1.81 mmol/L); OR 2) dose up-titrated to Alirocumab 150 mg Q2Wfrom Week 12 onwards until the last injection at Week 76, if the Week 8LDL-C was ≥70 mg/dL (1.81 mmol/L).

The follow-up period (if applicable) was a period of 8 weeks after theend of the DBTP for patients not consenting to participate in theopen-label extension study or if prematurely discontinuing studytreatment.

The laboratory measurement of lipid parameters were performed by acentral laboratory (central lab) during the study.

Patients who achieved 2 consecutive calculated LDL-C levels<25 mg/dL(0.65 mmol/L) during the study were monitored and managed.

Statin and other LMT (if applicable) should be stable (including dose)during the first 24 weeks of the DBTP barring exceptional circumstanceswhereby overriding concerns warrant such changes. At Week 24 onwards,background LMT may be modified only under certain conditions asdescribed below.

Patients should be on a stable diet (NCEP-ATPIII therapeutic lifestylechanges [TLC] diet or equivalent) throughout the entire study durationfrom screening. Table 1 provides a summary of the TLC diet for highcholesterol.

TABLE 1 Total Fat 25%-35% total calories* Saturated fat* <7% totalcalories Polyunsaturated fat up to 10% total calories Monounsaturatedfat up to 20% total calories Carbohydrates† 50%-60% total calories*Protein ~15% total calories Cholesterol <200 mg/day (5.172 mmol/day)Plant Sterols 2 g Soluble Fiber such as psyllium 10 g-25 g *ATP IIIallows an increase of total fat to 35 percent of total calories and areduction in carbohydrate to 50 percent for persons with the metabolicsyndrome. Any increase in fat intake should be in the form of eitherpolyunsaturated or monounsaturated fat. Trans-fatty acids are anotherLDL-raising fat that should be kept at a low intake. †Carbohydrateshould derive predominantly from foods rich in complex carbohydratesincluding grains-especially whole grains-fruits, and vegetables.

The study duration included a screening period of up to 3 weeks, a78-week DBTP for efficacy and safety assessment, and an 8-weekpost-treatment follow-up period after the last visit of the DBTP forpatients not consenting to participate in the open-label extension studyor if prematurely discontinuing study treatment. Thus, the maximum studyduration per patient was about 89 weeks (i.e., 20 months) (up to 3 weeksscreening+78 weeks double-blind treatment+8 weeks follow-up). The end ofthe study per patient was the last protocol planned visit or theresolution/stabilization of all SAEs, and AESI, whichever came last.

Selection of Patients

The inclusion criteria were: 1) patients with heFH* who were notadequately controlled with a maximally tolerated daily dose of statin**with or without other LMT, at stable dose prior to the screening visit(Week-3).

*Diagnosis of heFH must be made either by genotyping or by clinicalcriteria. For those patients not genotyped, the clinical diagnosis maybe based on either the Simon Broome criteria with a criteria fordefinite FH or the WHO/Dutch Lipid Network criteria with a score>8points.

According to the Simon Broome Register Diagnostic Criteria forHeterozygous Familial Hypercholesterolemia, definite familialhypercholesterolemia is defined as: 1) total-C>6.7 mmol/l (260 mg/dL) orLDL cholesterol above 4.0 mmol/l (155 mg/dL) in a child<16 years orTotal-C>7.5 mmol/l (290 mg/dL) or LDL cholesterol above 4.9 mmol/l (190mg/dL) in an adult. (Levels either pre-treatment or highest ontreatment); plus either A) tendon xanthomas in patient, or in 1st degreerelative (parent, sibling, child), or in 2nd degree relative(grandparent, uncle, aunt); or B) DNA-based evidence of an LDL receptormutation or familial defective Apo B.

According to the Simon Broome Register Diagnostic Criteria forHeterozygous Familial Hypercholesterolemia, possible familialhypercholesterolemia is defined as: 1) total-C>6.7 mmol/l (260 mg/dL) orLDL cholesterol above 4.0 mmol/l (155 mg/dL) in a child<16 years orTotal-C>7.5 mmol/l (290 mg/dL) or LDL cholesterol above 4.9 mmol/l (190mg/dL) in an adult. (Levels either pre-treatment or highest ontreatment); and at least one of the following: A) family history of MIbelow 50 years of age in 2nd degree relative or below 60 years of age in1st degree relative; and B) family history of raised cholesterols>7.5mmol/l (290 mg/dL) in adult 1st or 2nd degree relative or >6.7 mmol/l(260 mg/dL) in child or sibling under 16 years of age.

The WHO Criteria (Dutch Lipid Network clinical criteria) for diagnosisof Heterozygous Familial Hypercholesterolemia (heFH) is set forth inTable 2.

TABLE 2 Diagnostic Scoring for Heterozygous FamilialHypercholesterolemia Family history a First degree relative with knownpremature (men <55 1 yrs, women <60 yrs) coronary and vascular disease.b First degree relative with known LDL-cholesterol >95th percentile forage and sex. and/or a First degree relative with tendon xanthomata 2and/or arcus cornealis. b Children below 18 yrs. withLDL-cholesterol >95th percentile for age and sex. Clinical history aPatient has premature (men <55 yrs, women <60 2 yrs) coronary arterydisease b Patient has premature (men <55 yrs, women <60 1 yrs) cerebralor peripheral vascular disease. Physical examination a Tendon xanthomata6 b Arcus cornealis below the age of 45 yrs. 4 Laboratory analysismmol/L mg/dL a LDL-cholesterol >8.5 >330 8 b LDL-cholesterol 6.5-8.4250-329 5 c LDL-cholesterol 5.0-6.4 190-249 3 d LDL-cholesterol 4.0-4.9155-189 1 (HDL-cholesterol and triglycerides are normal) DNA-analysis aFunctional mutation low-density lipoprotein receptor gene present 8Diagnosis of heFH is: Certain When  >8 points Probable When 6-8 pointsPossible When 3-5 points **Definition of maximally tolerated dose (anyof the following were acceptable): 1) rosuvastatin 20 mg or 40 mg daily;2) atorvastatin 40 mg or 80 mg daily; 3) simvastatin 80 mg daily (ifalready on this dose for >1 year); or 4) patients not able to be on anyof the above statin doses, should be treated with the dose of dailyatorvastatin, rosuvastatin or simvastatin that is considered appropriatefor the patient as per the investigator's judgment or concerns. Someexamples of acceptable reasons for a patient taking a lower statin doseincluded, but were not limited to: adverse effects on higher doses,advanced age, low body mass index, regional practices, local prescribinginformation, concomitant medications, co-morbid conditions such asimpaired glucose tolerance/impaired fasting glucose.

Patients who met all of the above inclusion criteria were screened forthe following exclusion criteria, which are sorted and numbered in thefollowing 3 subsections: exclusion criteria related to studymethodology, exclusion criteria related to the active comparator and/ormandatory background therapies, and exclusion criteria related toAlirocumab.

Exclusion criteria related to study methodology were: 1) patient withoutdiagnosis of heFH made either by genotyping or by clinical criteria; 2)LDL-C<70 mg/dL (<1.81 mmol/L) at the screening visit (Week-3) andpatient with history of documented cardiovascular disease.Cardiovascular disease was defined as coronary heart disease, ischemicstroke or peripheral arterial disease; 3) LDL-C<100 mg/dL (<2.59 mmol/L)at the screening visit (Week-3) and patient without history ofdocumented cardiovascular disease; 4) not on a stable dose of LMT(including statin) for at least 4 weeks and/or fenofibrate for at least6 weeks, as applicable, prior to the screening visit (Week-3) and fromscreening to randomization; 5) currently taking a statin other thansimvastatin, atorvastatin, or rosuvastatin; 6) simvastatin,atorvastatin, or rosuvastatin is not taken daily or not taken at aregistered dose; 7) daily doses above atorvastatin 80 mg, rosuvastatin40 mg, or simvastatin 40 mg (except for patients on simvastatin 80 mgfor more than one year, who are eligible); 8) use of fibrates, otherthan fenofibrate within 6 weeks of the screening visit (Week3) orbetween screening and randomization visits; 9) use of nutraceuticalproducts or over-the-counter therapies that may affect lipids which havenot been at a stable dose/amount for at least 4 weeks prior to thescreening visit (Week-3) or between screening and randomization visits;10) use of red yeast rice products within 4 weeks of the screening visit(Week-3) or between screening and randomization visits; 11) patient whohas received plasmapheresis treatment within 2 months prior to thescreening visit (Week-3), or has plans to receive it during the study;12) recent (within 3 months prior to the screening visit [Week-3] orbetween screening and randomization visits) MI, unstable angina leadingto hospitalization, percutaneous coronary intervention (PCI), coronaryartery bypass graft surgery (CABG), uncontrolled cardiac arrhythmia,stroke, transient ischemic attack (TIA), carotid revascularization,endovascular procedure or surgical intervention for peripheral vasculardisease; 13) planned to undergo scheduled PCI, CABG, carotid, orperipheral revascularization during the study; 14) systolic BP>160 mmHgor diastolic BP>100 mmHg at screening visit or randomization visit; 15)history of New York Heart Association (NYHA) Class III or IV heartfailure within the past 12 months; 16) known history of a hemorrhagicstroke; 17) age<18 years or legal age of majority at the screening visit(Week-3), whichever is greater; 18) patients not previously instructedon a cholesterol-lowering diet prior to the screening visit (Week-3);19) newly diagnosed (within 3 calendar months prior to randomizationvisit [Week 0]) or poorly controlled (glycated haemoglobin A1c[HbA_(1c)]>9% at the screening visit [Week-3] diabetes); 20) presence ofany clinically significant uncontrolled endocrine disease known toinfluence serum lipids or lipoproteins. Note that patients on thyroidreplacement therapy can be included if the dosage has been stable for atleast 12 weeks prior to screening and between screening andrandomization visits, and TSH level is within the normal range of theCentral Laboratory at the screening visit; 21) history of bariatricsurgery within 12 months prior to the screening visit (Week-3); 22)unstable weight defined by a variation >5 kg within 2 months prior tothe screening visit (Week-3); 23) known history of homozygous FH; 24)known history of loss of function of PCSK9 (i.e., genetic mutation orsequence variation); 25) use of systemic corticosteroids, unless used asreplacement therapy for pituitary/adrenal disease with a stable regimenfor at least 6 weeks prior to randomization visit (Week 0). Note thattopical, intra-articular, nasal, inhaled and ophthalmic steroidtherapies were not considered as ‘systemic’ and were allowed; 26) use ofcontinuous estrogen or testosterone hormone replacement therapy unlessthe regimen has been stable in the past 6 weeks prior to the Screeningvisit (Week-3) and no plans to change the regimen during the study; 27)history of cancer within the past 5 years, except for adequately treatedbasal cell skin cancer, squamous cell skin cancer or in situ cervicalcancer; 28) known history of a positive HIV test; 29) patient who hastaken any investigational drugs other than the Alirocumab trainingplacebo kits within 1 month or 5 half lives, whichever is longer; 30)patient who has been previously treated with at least one dose ofAlirocumab or any other anti-PCSK9 monoclonal antibody in other clinicaltrials; 31) patient who withdraws consent during the screening period(patient who is not willing to continue or fails to return); 32)conditions/situations such as: a) any clinically significant abnormalityidentified at the time of screening that, in the judgment of theInvestigator or any sub-Investigator, would preclude safe completion ofthe study or constrain endpoints assessment; e.g., major systemicdiseases, patients with short life expectancy; or b) considered by theInvestigator or any sub-Investigator as inappropriate for this study forany reason, e.g.: deemed unable to meet specific protocol requirements,such as scheduled visits; deemed unable to administer or toleratelong-term injections as per the patient or the Investigator;Investigator or any sub-Investigator, pharmacist, study coordinator,other study staff or relative thereof directly involved in the conductof the protocol, etc; presence of any other conditions (eg, geographicor social), either actual or anticipated, that the Investigator feelswould restrict or limit the patient's participation for the duration ofthe study; or 33) laboratory findings during screening period (notincluding randomization Week 0 labs): positive test for Hepatitis Bsurface antigen or Hepatitis C antibody; positive serum beta-hCG orurine pregnancy test (including Week 0) in women of childbearingpotential (WOCBP); triglycerides>400 mg/dL (>4.52 mmol/L) (1 repeat labis allowed); estimated glomerular filtration rate (eGFR)<30 mL/min/1.73m2 according to 4-variable modification of diet in renal disease (MDRD)Study equation (calculated by central lab); alanine aminotransferase(ALT) or aspartate aminotransferase (AST)>3×upper limit of normal range(ULN) (1 repeat lab is allowed); CPK>3 x ULN (1 repeat lab is allowed);TSH<lower limit of normal (LLN) or >ULN (1 repeat lab is allowed).

Exclusion criteria related to the active comparator and/or mandatorybackground therapies were: 1) all contraindications to the backgroundtherapies or warnings/precautions of use (when appropriate) as displayedin the respective National Product Labeling.

Exclusion criteria related to Alirocumab were: 1) known hypersensitivityto monoclonal antibody or any component of the drug product; 2) pregnantor breast-feeding women; or 3) women of childbearing potential notprotected by highly-effective method(s) of birth control (as defined inthe informed consent form and/or in a local protocol addendum) and/orwho are unwilling or unable to be tested for pregnancy. Note that womenof childbearing potential must have a confirmed negative pregnancy testat screening and randomization visits. They must use an effectivecontraceptive method throughout the entire duration of the studytreatment, and for 10 weeks after the last intake of IMP, and agree torepeat urine pregnancy test at designated visits. Postmenopausal womenmust be amenorrheic for at least 12 months.

Coronary heart disease, ischemic stroke, and peripheral arterialdisease, as defined in exclusion criteria number 2 related to studymethodology was as follows. Documented history of CHD (includes one ormore of the following): acute myocardial infarction (MI); silentmyocardial infarction; unstable angina; coronary revascularizationprocedure (eg, percutaneous coronary intervention [PCI] or coronaryartery bypass graft surgery [CABG]); clinically significant CHDdiagnosed by invasive or non-invasive testing (such as coronaryangiography, stress test using treadmill, stress echocardiography ornuclear imaging).

Documented previous ischemic stroke with a focal ischemic neurologicaldeficit that persisted more than 24 hours, considered as being ofatherothrombotic origin. CT or MRI must have been performed to rule outhemorrhage and non-ischemic neurological disease.

Documented peripheral arterial disease (one of the following criteriamust be satisfied): 1) current intermittent claudication (musclediscomfort in the lower limb produced by exercise that is bothreproducible and relieved by rest within 10 minutes) of presumedatherosclerotic origin together with ankle-brachial index equal to orless than 0.90 in either leg at rest or 2) history of intermittentclaudication (muscle discomfort in the lower limb produced by exercisethat is both reproducible and relieved by rest within 10 minutes)together with endovascular procedure or surgical intervention in one orboth legs because of atherosclerotic disease or 3) history of criticallimb ischemia together with thrombolysis, endovascular procedure orsurgical intervention in one or both legs because of atheroscleroticdisease.

Study Treatments

Sterile Alirocumab drug product was supplied at a concentration of 75mg/mL and 150 mg/mL both as 1 mL volume in an auto-injector. The drugsubstance was formulated in histidine, pH 6.0, polysorbate 20, andsucrose.

Sterile placebo for Alirocumab was prepared in the same formulation asAlirocumab without the addition of protein as 1 mL volume in anauto-injector.

During the double-blind treatment period, Alirocumab or placebo wasadministered subcutaneously Q2W, starting at Week 0 continuing up to thelast injection (Week 76) 2 weeks before the end of the double blindtreatment period (DBTP). If the injection was scheduled to take place onthe same date as the site visit, then the IMP was administered after theblood sampling was completed.

Investigational Medicinal Product (IMP) should ideally have beenadministered Q2W subcutaneously at approximately the same time of theday; however it was acceptable to have a window period of±3 days. Thetime of the day was based on the patient's preference.

The following classes of drugs were identified as non-NIMP because themedication was either a background therapy or a potential rescuemedication: statins (rosuvastatin, atorvastatin, simvastatin);cholesterol absorption inhibitors (ezetimibe); bile acid-bindingsequestrants (such as cholestyramine, colestipol, colesevelam);nicotinic acid; fenofibrate; and omega-3 fatty acids (≥1000 mg daily).

Patients were randomized to receive either placebo or Alirocumab duringthe double-blind study treatment period using a ratio 1:2, withpermuted-block randomization. Randomization was stratified according toprior history of MI or ischemic stroke [Yes/No], statin treatment(atorvastatin 40 to 80 mg daily or rosuvastatin 20 to 40 mg daily vs.simvastatin whatever the daily dose, atorvastatin below 40 mg daily orrosuvastatin below 20 mg daily) and geographic region.

A concomitant medication was any treatment received by the patientconcomitantly to the study (until follow-up visit). Concomitantmedications should be kept to a minimum during the study. However, ifthese are considered necessary for the patient's welfare and areunlikely to interfere with the IMP, they may be given at the discretionof the Investigator, with a stable dose (when possible). Besides thespecific information related to concomitant medications provided in thissection, any other concomitant medication(s) will be allowed. If thepatient has an LDL-C≥160 mg/dL (4.14 mmol/L) at the screening visit(Week-3) and is treated with a statin only, i.e., without additionalLMT, the investigator will have to report the reason for the patient notbeing on a second LMT. For background LMT, including statins, sites mustfollow the national product label for the safety monitoring andmanagement of patients.

Nutraceutical products or over-the-counter therapies that may affectlipids were allowed only if they had been used at a stable dose for atleast 4 weeks prior to screening visit, during the screening period andmaintained during the first 24 weeks of the double-blind treatmentperiod. After the Week 24 visit, modification to these nutraceuticalproducts or over-the-counter therapies was allowed but in general shouldbe avoided. Examples of such nutraceutical products or over-the-countertherapies include omega-3 fatty acids at doses<1000 mg, plant stanolssuch as found in Benecol, flax seed oil, and psyllium.

Patients must have been on stable maximally tolerated daily registereddoses of statins with or without other LMT for at least 4 weeks (6 weeksfor fenofibrate) before screening visit. During the study, the patientsshould stay on these stable maximally tolerated registered daily dosesof statins with or without other LMT. From the screening visit (Week-3)until Week 24 of the double-blind treatment period, the background LMTshould not be changed. No dose adjustment, discontinuation or initiationof other statins or other LMT should take place during this time,barring exceptional circumstances whereby overriding concerns (includingbut not limited to triglyceride alert posted by the central lab) warrantsuch changes, as per the Investigator's judgment.

For a rescue notification of LDL-C at the Week 24 visit and later, i.e.,LDL-C increase>25% as compared to randomization visit LDL-C on twoconsecutive occasions, the Investigator should have ensured that noreasonable explanation existed for insufficient LDL-C control (such asan alternative medical cause like corticosteroid use, etc) and inparticular that: compliance with diet was appropriate; compliance withbackground LMT was appropriate; and study treatment was given asplanned. If any of the above could reasonably explain the insufficientLDL-C control, the Investigator should have undertaken appropriateaction, i.e., stress on the absolute need to be compliant withtreatment, if needed organize a specific interview with a qualifiednutrition professional and stress on the absolute need to be compliantwith diet, and perform a blinded LDL-C assessment within 1 to 2 months.If none of the above mentioned reasons were found, or if appropriateaction failed to decrease LDL-C under the alert value, rescue medicationmay have been introduced.

If no reason for LDL-C above the threshold value could be found, or ifappropriate action failed to decrease LDL-C below the threshold value,rescue medication may have been introduced. The effectiveness of anysuch changes was to be made based on lack of rescue threshold fromblinded lipid testing at the next routinely scheduled lab draw. Patientsper protocol already received a maximum tolerated dose of statin, sostatin uptitration or switch was not an option. For further LDL-Clowering, the investigator could consider adding: a cholesterolabsorption inhibitor (ezetimibe), or a bile acid-binding sequestrant(the resins cholestyramine and colestipol, or colesevelam, anonabsorbable polymer). The following lipid-modifying agents could alsobe considered: fibrate (Note: Caution should be exercised when combiningfibrates with other cholesterol-lowering medications such as statinsbecause of the risk of myopathy. When a fibrate is combined with astatin, fenofibrate is the fibrate of choice because it does not affectstatin glucuronidation. The only fibrate allowed per protocol wasfenofibrate); nicotinic acid (niacin) (Note: Niacin raises blood glucosebut has been shown to be effective in modifying lipid disorders inpeople with diabetes if glucose control is maintained).

In summary, background LMT should not be modified from screening to thefollow-up visit. However, up to Week 24, if a confirmed TG alert wasreached or if there was an overwhelming clinical concern (at thediscretion of the Investigator) then modification of the background LMTwas allowed. At Week 24 onwards, if a confirmed TG alert was reached, orif a rescue threshold for LDL-C was attained (and no other reasonableexplanation exists), or if there was an overwhelming clinical concern(at the discretion of the Investigator) then modification of thebackground LMT was allowed.

Women of childbearing potential must take an effective contraceptivemethod throughout the study treatment and for 10 weeks after the lastIMP injection (e.g., Follow-up visit).

Forbidden concomitant medications from the initial screening visit untilthe follow-up visit included the following: statins other thansimvastatin, atorvastatin and rosuvastatin; fibrates, other thanfenofibrate; and red yeast rice products.

Study Endpoints

The primary efficacy endpoint was the percent change in calculated LDL-Cfrom baseline to Week 24, which was defined as: 100× (calculated LDL-Cvalue at Week 24 -calculated LDL-C value at baseline)/calculated LDL-Cvalue at baseline. The baseline calculated LDL-C value was the lastLDL-C level obtained before the first double-blind IMP injection. Thecalculated LDL-C at Week 24 was the LDL-C level obtained within the Week24 analysis window and during the main efficacy period. The mainefficacy period was defined as the time from the first double-blind IMPinjection up to 21 days after the last double-blind IMP injection or upto the upper limit of the Week 24 analysis window, whichever came first.All calculated LDL-C values (scheduled or unscheduled, fasting or notfasting) may be used to provide a value for the primary efficacyendpoint if appropriate according to above definition.

The key secondary efficacy endpoints were: 1) the percent change incalculated LDL-C from baseline to Week 12: similar definition and rulesas for primary efficacy endpoint, except that the calculated LDL-C atWeek 12 was the LDL-C level obtained within the Week 12 analysis windowand during the 12-week efficacy period. The 12-week efficacy period wasdefined as the time from the first double-blind IMP injection up to theVisit 6 re-supply IVRS contact or up to 21 days after the lastdouble-blind IMP injection, whichever came first. Blood samplingcollected the day of the Visit 6 re-supply IVRS contact was consideredas before titration; 2) the percent change in Apo B from baseline toWeek 24, using the same definition and rules as for the primaryendpoint; 3) the percent change in non-HDL-C from baseline to Week 24,using the same definition and rules as for the primary endpoint; 4) thepercent change in total-C from baseline to Week 24, using the samedefinition and rules as for the primary endpoint; 5) the percent changein Apo B from baseline to Week 12, using the same definition and rulesas for the percent change in calculated LDL-C from baseline to Week 12;6) the percent change in non-HDL-C from baseline to Week 12, using thesame definition and rules as for the percent change in calculated LDL-Cfrom baseline to Week 12; 7) the percent change in total-C from baselineto Week 12, using the same definition and rules as for the percentchange in calculated LDL-C from baseline to Week 12; 8) the percentchange in calculated LDL-C from baseline to Week 52, using definitionsand rules that were similar to the ones used for the primary endpointreplacing Week 24 by Week 52. Note that the 52-week efficacy period wasdefined as the time from the first double-blind IMP injection up to 21days after the last double-blind IMP injection, or up to the upper limitof the Week 52 analysis window, whichever came first; 9) the proportionof patients reaching LDL-C goal at Week 24, i.e., LDL-C<70 mg/dL (1.81mmol/L) in case of prior CVD or <100 mg/dL (2.59 mmol/L) for patientswithout prior CVD, defined as: (number of patients whose calculatedLDL-C value at Week 24 reach LDL-C goal/number of patients in themodified intent-to-treat (mITT) population)*100, using definition andrules used for the primary endpoint; 10) the proportion of patientsreaching LDL-C<70 mg/dL (1.81 mmol/L) at Week 24; 11) the percent changein Lp(a) from baseline to Week 24, using the same definition and rulesas for the primary endpoint; 12) the percent change in HDL-C frombaseline to Week 24, using the same definition and rules as for theprimary endpoint; 13) the percent change in HDL-C from baseline to Week12, using the same definition and rules as for the percent change incalculated LDL-C from baseline to Week 12; 14) the percent change inLp(a) from baseline to Week 12, using the same definition and rules asfor the percent change in calculated LDL-C from baseline to Week 12; 15)the percent change in fasting TG from baseline to Week 24, using thesame definition and rules as for the primary endpoint; 16) the percentchange in fasting TG from baseline to Week 12, using the same definitionand rules as for the percent change in calculated LDL-C from baseline toWeek 12; 17) the percent change in Apo A-1 from baseline to Week 24,using the same definition and rules as for the primary endpoint; and 18)the percent change in Apo A-1 from baseline to Week 12, using the samedefinition and rules as for the percent change in calculated LDL-C frombaseline to Week 12.

Other secondary efficacy endpoints were: 1) the percent change incalculated LDL-C from baseline to Week 78, using definitions and rulesthat were similar to the ones used for the primary endpoint replacingWeek 24 by Week 78. The 78-week efficacy period was defined as the timefrom the first double-blind IMP injection up to 21 days after the lastdouble-blind IMP injection, or up to the upper limit of the Week 78analysis window, whichever came first; 2) the proportion of patientsreaching LDL-C goal at Weeks 12, 52, and 78, i.e., LDL-C<70 mg/dL (1.81mmol/L) in case of prior CVD or <100 mg/dL (2.59 mmol/L) for patientswithout prior CVD; 3) the proportion of patients reaching LDL-C<100mg/dL (2.59 mmol/L) at Week 24; 4) the proportion of patients reachingLDL-C<100 mg/dL (2.59 mmol/L) at Week 12; 5) the proportion of patientsreaching LDL-C<70 mg/dL (1.81 mmol/L) at Week 12; 6) the absolute changein calculated LDL-C (mg/dL and mmol/L) from baseline to Weeks 12, 24,52, and 78; 7) the percent change in Apo B, non-HDL-C, total-C, Lp (a),HDL-C, fasting TG, and Apo A-1 from baseline to Weeks 52 and 78; 8) thechange in ratio Apo B/Apo A-1 from baseline to Weeks 12, 24, 52, and 78;9) the proportion of patients with Apo B<80 mg/dL (0.8 g/L) at Weeks 12,24, 52, and 78; 10) the proportion of patients with non-HDL-C<100 mg/dLat Weeks 12, 24, 52, and 78; and 11) the proportion of patients withcalculated LDL-C<70 mg/dL (1.81 mmol/L) and/or ≥50% reduction incalculated LDL-C (if calculated LDL-C≥70 mg/dL [1.81 mmol/L]) at Weeks12, 24, 52, and 78.

Other endpoints were: anti-Alirocumab antibody assessments,high-sensitivity C-reactive protein, glycated haemoglobin A1c, EQ-5DQuestionnaire, pharmacogenetics, and pharmacokinetics. Anti-Alirocumabantibodies included the antibody status (positive/negative) and antibodytiters. Serum samples for anti-Alirocumab antibody determination weredrawn periodically throughout the study. The first scheduled sample atrandomization visit was obtained before IMP injection (predose).Patients who had a titer at or above 240 for anti-Alirocumab antibody atfollow-up visit had additional antibody sample(s), at 6 to 12 monthsafter the last dose and thereafter, about every 3 to 6 months untiltiter returns below 240. The percent change in high-sensitivityC-reactive protein (hs-CRP) was measured at baseline and Weeks 24, 52,and 78. EQ-5D is a standardized measure of health status developed bythe EuroQol Group in order to provide a simple, generic measure ofhealth for clinical and economic appraisal. The EQ-5D as a measure ofhealth-related quality of life defines health in terms of 5 dimensions:mobility, self-care, usual activities, pain/discomfort,anxiety/depression. Each dimension can take one of three responses (3ordinal levels of severity): “no problem” (1); “some problems” (2);“severe problems” (3); Overall health state is defined as a 5-digitnumber. Health states defined by the 5-dimensional classification can beconverted into corresponding index scores that quantify health status,where 0 represents ‘death’ and 1 represents “perfect health”.

Study Procedures

For all visits after Day 1/Week 0 (randomization visit), a timeframe ofa certain number of days was allowed. The window period for visits atWeeks 12 and 24 were ±3 days, at Weeks 52 and 78 was ±5 days, and forall other site visits it was ±7 days during the double-blind treatmentperiod, and follow-up period. A window period of +3 days was allowed forthe randomization visit (Day1/Week 0) and±7 days for the injectiontraining visit during the screening period (Week-1). For all visitsafter Day 1/randomization visit, if one visit date is changed, then thenext visit should take place according to the original schedule.

Safety

Occurrence of treatment emergent adverse events (TEAEs) reported by thepatient or noted by the investigator, serious adverse events (SAEs),TEAEs leading to treatment discontinuation, AEs of special interest(local Injection site reactions, allergic events, selected neurologicalevents and cardiovascular events confirmed by adjudication result),occurrence of PCSA (potentially clinically significant abnormalities) inlaboratory parameters, exploratory analysis for patients with 2consecutive calculated LDL-C<25 mg/dL (<0.65 mmo/L) and for changes inblood glucose control, including diabetes.

Statistical Methods Sample Size Determination:

A total sample size of 45 patients (30 in alirocumab and 15 in placebo)had 95% power to detect a difference in mean percent change in LDL-C of30% with a 0.05 two-sided significance level and assuming a commonstandard deviation of 25%, and all these 45 patients having an evaluableprimary endpoint. Nevertheless, to meet regulatory requirements acrossthe program, the sample size was increased to assess the safety ofalirocumab. In order to have at least 225 patients on alirocumabfollowed for 12 months in this study, and assuming a drop-out rate of10% over the first 3-month period and a drop-out rate of 20% over theremaining 9-month period, the final total sample size was increased to471 with a randomization ratio 2:1 (alirocumab 314:placebo 157).

Timing of Analyses:

The first step analysis included efficacy endpoints up to Week 52 (finalefficacy analysis) and interim safety analysis, which was performed onall safety data up to the common study cut-off date (last patient Week52 visit). Analysis of lipid data beyond Week 52 was descriptive. Theseresults are presented herein.

The second step (final) analysis will be conducted at the end of thestudy and will consist in the final analysis of efficacy endpoints up toWeek 78 and final safety analysis.

Analysis Populations:

The primary efficacy analysis population was the intent-to-treat (ITT)population, defined as all randomized patients who had an evaluableprimary endpoint, that is, those with an available baseline calculatedLDL-C value, and at least one available calculated LDL-C value withinone of the analysis windows up to Week 24 (including all calculatedLDL-C values on-treatment and off-treatment).

The secondary efficacy analysis population was the modifiedintent-to-treat (mITT) population, defined as all randomized patientswho took at least one dose or part of a dose of the double-blindinvestigational medicinal product (IMP) and who had an availablecalculated LDL-C value at baseline and at least one within one of theanalysis windows up to Week 24 during the efficacy treatment period. Theefficacy treatment period was defined as the time from the firstdouble-blind IMP injection up to 21 days after the last double-blindinjection.

The safety population included all randomized patients who received atleast one dose or part of a dose of the double-blind IMP.

Efficacy Analyses:

Primary analyses of efficacy endpoints were conducted using an ITTapproach (based on the ITT population defined above), including alllipid data, regardless of whether the patient was continuing therapy ornot. This corresponds to ITT estimands, defined for primary and keysecondary endpoints. In addition, analyses were also conducted using anon-treatment approach (based on the mITT population defined above),including lipid data collected during the efficacy treatment period.This corresponds to on-treatment estimands of key secondary endpoints.

The ITT approach analyzed all patients, irrespective of their adherenceto the treatment; it assessed the benefit of the treatment strategy andreflected as much as possible the effect in a population of patients.The on-treatment approach analyzed the effect of treatment, restrictedto the period during which patients actually received the treatment. Itassessed the benefit that a treatment would achieve in patients adherentto treatment up to the considered time point.

Efficacy analyses were performed according to treatment as-randomized.

All measurements, scheduled or unscheduled, fasting or not fasting, wereassigned to analysis windows in order to provide an assessment for Week4 to Week 78 time points.

With regards to the primary efficacy analysis (ITT approach), thepercent change in calculated LDL-C from baseline to Week 24 was analyzedusing a mixed-effect model with repeated measures (MMRM) approach. Allpost-baseline data available from Week 4 to Week 52 analysis windowswere used and missing data were accounted for by the MMRM. The modelincluded the fixed categorical effects of treatment group (placeboversus alirocumab), randomization strata (as per IVRS), time point (Week4 to Week 52), treatment-by-time point interaction and strata-by-timepoint interaction, as well as the continuous fixed covariates ofbaseline LDL-C value and baseline value-by-time-point interaction. Thismodel provided baseline adjusted least-squares means (LSmeans) estimatesat Week 24 for both treatment groups with their corresponding standarderrors and 95% confidence intervals. To compare the alirocumab to theplacebo group, an appropriate contrast statement was used to test thedifferences of these estimates at the 5% alpha level.

A hierarchical procedure was defined to test key secondary endpointswhile controlling for multiplicity (using above order of key secondaryendpoints). The first key secondary endpoint was the percent change incalculated LDL-C from baseline to Week 24 using an on-treatmentapproach.

Continuous secondary variables anticipated to have a normal distribution(i.e., lipids other than TGs and Lp(a)) were analyzed using the sameMMRM model as for the primary endpoint. Continuous endpoints anticipatedto have a non-normal distribution (i.e., TGs and Lp(a)) were analyzedusing multiple imputation approach for handling of missing valuesfollowed by robust regression model with endpoint of interest asresponse variable using M-estimation (using SAS ROBUSTREG procedure)with treatment group, randomization strata (as per IVRS) andcorresponding baseline value(s) as effects to compare treatment effects.Combined estimate for mean in both treatment groups, as well as thedifferences of these estimates, with their corresponding SEs, 95% CIsand p-value were provided (through SAS MIANALYZE procedure).

Binary secondary efficacy endpoints were analyzed using multipleimputation approach for handling of missing values followed bystratified logistic regression with treatment group as main effect andcorresponding baseline value(s) as covariate, stratified byrandomization factors (as per IVRS). Combined estimates of odds ratioversus placebo, 95% CI, and p-value were provided (through SAS MIANALYZEprocedure).

Safety Analyses:

Safety analyses were descriptive, performed on the safety populationaccording to treatment actually received. The safety analysis focused onthe TEAE period defined as the time from the first dose of double-blindIMP up to 70 days after the last double-blind injection. TEAE whichdeveloped, worsened or became serious or PCSA occurring after thepatient inclusion in the open-label extension study (LTS13643) were notconsidered in the TEAE period. TEAE period was truncated at the commonstudy cut-off date.

Results Study Patients Patient Accountability

Of the 486 randomized patients (323 patients and 163 patients in thealirocumab and the placebo groups, respectively), one patient in thealirocumab group was not treated and was therefore not included in thesafety population. This patient was also excluded from the ITTpopulation (no LDL-C value within one of the analysis windows up to Week24 as the patient withdrew consent on Day 1).

Two randomized patients in the alirocumab group were excluded from themITT population (one patient excluded from the ITT population and onepatient with no LDL-C value within one of the analysis windows up toWeek 24 during the efficacy treatment period).

TABLE 3 Analysis populations Alirocumab 75 Q2W/Up150 Placebo Q2W AllRandomized population 163 (100%) 323 (100%)  486 (100%)  Efficacypopulations Intent-to-Treat (ITT) 163 (100%) 322 (99.7%) 485 (99.8%)Modified Intent-to-Treat 163 (100%) 321 (99.4%) 484 (99.6%) (mITT)Safety population 163 322 485 Note: The safety population patients aretabulated according to treatment actually received (as treated). For theother populations, patients are tabulated according to their randomizedtreatment.

In the alirocumab group, among the 311 patients who received at leastone injection after Week 12, 135 (43.4%) patients received automaticup-titration at Week 12 from alirocumab 75 mg Q2W to 150 mg Q2W in ablinded manner.

Study Disposition

Study disposition, exposure and safety analyses were assessed using alldata up to the study common cut-off date (defined as the date of thelast patient's Week 52 visit). Therefore, this first step analysisincludes data beyond Week 52 and up to Week 78 or Follow-up visit forsome patients.

There were in total 7 (1.4%) randomized patients who completed the78-week double-blind study treatment period and 424 (87.2%) randomizedpatients with treatment ongoing at the time of the first-step analysiscut-off date. The double-blind IMP was prematurely discontinued beforeWeek 78 for 18 (11.0%) randomized patients in the placebo group and 36(11.1%) randomized patients in the alirocumab group. The main reasonsfor study treatment discontinuation were adverse event and otherreasons.

In addition, among these patients 34 (10.5%) randomized patients hadprematurely discontinued the double-blind IMP before the Week 52 visitin the alirocumab group and 15 (9.2%) patients in the placebo group.

In this first step analysis, final results are available for the primaryefficacy endpoint at Week 24 and key secondary efficacy endpoints wereassessed at Week 12, Week 24 and Week 52. The primary endpoint wasmissing for 46 patients at the week 24 visit for the following reasons:18 samples were not done due to earlier study discontinuation, 14samples were done outside the analysis time window, 4 missing sampleswhile visit Week 24 was done, and 10 samples were done but themeasurement could not be done (lipemia, insufficient quantity, TGs>400mg/dL[>4.52 mmol/L], sample lost, . . . ).

Demographics, Baseline, and Summary Population Characteristics

Demographic characteristics, disease characteristics and lipidparameters at baseline were similar in the alirocumab group as comparedto the placebo group (see Table 4). 486 heFH patients diagnosed bygenotyping (39%) or WHO or Simon Broome criteria (61%) were randomized(2:1) to alirocumab (75 mg Q2W potentially uptitrated to 150 mg Q2W) orplacebo (323 versus 163, respectively). Half of the randomizedpopulation (51%) had a history of at least one coronary heart disease(CHD) or multiple CHD risk factors that defined these patients being atvery high cardiovascular risk. Demographics characteristics, diseasecharacteristics and lipid parameters at baseline were similar in thealirocumab group as compared to the placebo group. All patients weretreated with a statin, 82% receiving a dose defined as high intensitystatin (atorvastatin 40 to 80 mg daily or rosuvastatin 20 to 40 mgdaily) and 57% receiving ezetimibe in addition to the statin. Mean (SD)calculated LDL-C at baseline was 144.6 (49.7) mg/dL [3.75 (1.29)mmol/L].

Exposure to injections was similar across treatment groups with a meanexposure of 59 weeks. In the alirocumab group, among the 311 patientswho received at least one injection after Week 12, 135 (43.4%) patientsreceived automatic up-titration at Week 12 from alirocumab 75 mg Q2W to150 mg Q2W in a blinded manner.

TABLE 4 Baseline Characteristics of FHI Patient Population AlirocumabPlacebo Characteristic (N = 323) (N = 163) Diagnosis of heFH^(†), % (n)Genotyping 39.9% (129) 38.0% (62) Clinical criteria 59.8% (193) 62.0%(101) Age, mean (SD), yrs 52.1 (12.9) 51.7 (12.3) Male 55.7% (180) 57.7%(94) Race, white 92.9% (300) 88.3% (144) BMI, mean (SD), kg/m² 29.0(4.6) 30.0 (5.4) CHD history 45.5% (147) 47.9% (78) CHD riskequivalents^(†) 16.7% (54) 15.3% (25) Current smoker 12.1% (39) 18.4%(30) Hypertension 43.0% (139) 43.6% (71) Type 2 diabetes 9.6% (31) 15.3%(25) % (N) of patients unless statedAll pts on background of maxtolerated statin ± other lipid-lowering therapy. ^(†)Diagnosis of heFHmust be made either by genotyping or by clinical criteria. For thosepatients not genotyped, the clinical diagnosis may be based on eitherthe Simon Broome criteria for definite FH or the WHO/Dutch Lipid Networkcriteria with a score of >8 points. In FH I, one patient was categorisedas “probable” FH by clinical criteria - genotyping results for thispatient are pending.

TABLE 5 Disease characteristics and other relevant baseline data -Randomized population Alirocumab 75 Placebo Q2W/Up150 Q2W All (N = 163)(N = 323) (N = 486) Type of hypercholesterolemia Heterozygous FamilialHypercholesterolemia (heFH) 163 (100%)  323 (100%)  486 (100%) Non-Familial Hypercholesterolemia (non-FH)  0  0  0 Time fromhypercholesterolemia diagnosis (years) Number 163 323 486 Mean (SD)13.28 (11.38)  12.19 (11.38)  12.55 (11.38)  Median    9.43    8.82   9.03 Min:Max 0.0:42.6 0.0:60.7 0.0:60.7 Confirmation of diagnosis Bygenotyping  62 (38.0%) 129 (39.9%) 191 (39.3%) By WHO/Simon Broome^(a)101 (62.0%) 193 (59.8%) 294 (60.5%) ^(a)for heFH diagnosis not confirmedby genotyping. Note: at time of screening, one patient was includedbased on clinical criteria with a score of 8 for the WHO criteria. Asthe clinical score characterized the patient as probable heFH ratherthan certain, a genotyping was performed to confirm heFH status butthese results are still pending.

TABLE 6 Cardiovascular History and Risk Factors Breakdown AlirocumabPlacebo Characteristic (N = 323) (N = 163) CHD history 45.5% (147) 47.9%(78) Acute MI 22.0% (71) 26.4% (43) Silent MI 2.5% (8) 1.2% (2) Unstableangina 11.1% (36) 15.3% (25) Coronary revasc. 31.6% (102) 34.4% (56)Other clinically significant CHD 26.9% (87) 29.4% (48) CHD riskequivalents 16.7% (54) 15.3% (25) Ischemic stroke 4.0% (13) 1.8% (3)Peripheral arterial disease 2.8% (9) 2.5% (4) Moderate CKD 6.2% (20)5.5% (9) Diabetes + 2 or more risk factors 5.9% (19) 6.1% (10) % (N) ofpatients unless stated. All pts on background of max tolerated statin ±other lipid-lowering therapy

TABLE 7 Background LMT at randomization - Randomized populationAlirocumab 75 Placebo Q2W/Up150 Q2W All (N = 163) (N = 323) (N = 486)Any statin 163 (100%) 323 (100%) 486 (100%) Taking high 135 (82.8%) 261(80.8%) 396 (81.5%) intensity statin Atorvastatin daily 64 (39.3%) 113(35.0%) 177 (36.4%) dose (mg) 10 1 (0.6%) 3 (0.9%) 4 (0.8%) 20 2 (1.2%)7 (2.2%) 9 (1.9%) 40 23 (14.1%) 23 (7.1%) 46 (9.5%) 80 38 (23.3%) 77(23.8%) 115 (23.7%) Other doses 0 3 (0.9%) 3 (0.6%) Rosuvastatin 81(49.7%) 172 (53.3%) 253 (52.1%) daily dose (mg)  5 4 (2.5%) 7 (2.2%) 11(2.3%) 10 2 (1.2%) 5 (1.5%) 7 (1.4%) 20 19 (11.7%) 44 (13.6%) 63 (13.0%)40 55 (33.7%) 116 (35.9%) 171 (35.2%) Other doses 1 (0.6%) 0 1 (0.2%)Simvastatin daily 18 (11.0%) 38 (11.8%) 56 (11.5%) dose (mg) 10 2 (1.2%)2 (0.6%) 4 (0.8%) 20 1 (0.6%) 5 (1.5%) 6 (1.2%) 40 10 (6.1%) 25 (7.7%)35 (7.2%) 80 3 (1.8%) 6 (1.9%) 9 (1.9%) Other doses 2 (1.2%) 0 2 (0.4%)Any LMT other 107 (65.6%) 198 (61.3%) 305 (62.8%) than statins^(a) AnyLMT other 105 (64.4%) 192 (59.4%) 297 (61.1%) than nutra- ceuticalsEzetimibe 97 (59.5%) 180 (55.7%) 277 (57.0%) Nutraceuticals 8 (4.9%) 20(6.2%) 28 (5.8%) ^(a)in combination with statins or not. High intensitystatin corresponds to atorvastatin 40 to 80 mg daily or rosuvastatin 20to 40 mg daily.

TABLE 8 Lipid efficacy parameters at baseline - Quantitative summary inconventional units - Randomized population Alirocumab 75 PlaceboQ2W/Up150 Q2W All (N = 163) (N = 323) (N = 486) Calculated LDL-C (mg/dL)Number 163 323 486 Mean (SD) 144.4 (46.8) 144.8 (51.1) 144.6 (49.7)Median   138.0   135.0   135.5 Q1:Q3 112.0:166.0 112.0:163.0 112.0:165.0Min:Max  66:354  39:384  39:384 Measured LDL-C (mg/dL) Number 140 272412 Mean (SD) 140.0 (43.5) 140.2 (49.7) 140.1 (47.6) Median   135.0  130.5   132.0 Q1:Q3 111.0:164.0 108.0:159.5 108.5:161.0 Min:Max 68:356  37:378  37:378 Non-HDL-C (mg/dL) Number 163 323 486 Mean (SD)169.6 (50.6) 170.3 (54.6) 170.1 (53.3) Median   161.0   158.0   160.0Q1:Q3 132.0:195.0 134.0:198.0 133.0:196.0 Min:Max  78:390  58:426 58:426 Total-C (mg/dL) Number 163 323 486 Mean (SD) 217.6 (50.3) 221.1(54.3) 219.9 (53.0) Median   210.0   212.0   211.0 Q1:Q3 185.0:240.0184.0:244.0 185.0:243.0 Min:Max 137:445 123:482 123:482 HDL-C (mg/dL)Number 163 323 486 Mean (SD)  48.0 (14.4)  50.8 (15.7)  49.8 (15.3)Median   45.0   47.0   46.5 Q1:Q3 36.0:56.0 39.0:59.0 38.0:58.0 Min:Max 24:116  22:115  22:116 Fasting TGs (mg/dL) Number 163 323 486 Mean (SD)126.5 (62.9) 128.4 (66.7) 127.8 (65.4) Median   111.0   113.0   112.0Q1:Q3  85.0:151.0  82.0:153.0  83.0:152.0 Min:Max  45:431  35:566 35:566 Lipoprotein-(a)(mg/dL) Number 161 317 478 Mean (SD)  47.2 (51.6) 51.7 (50.2)  50.2 (50.7) Median   23.0   34.0   28.0 Q1:Q3  8.0:72.012.0:82.0 11.0:80.0 Min:Max  2:223  2:229  2:229 Apo-B (mg/dL) Number161 317 478 Mean (SD) 113.4 (28.5) 114.4 (30.8) 114.1 (30.0) Median  109.0   108.0   109.0 Q1:Q3  94.0:128.0  94.0:130.0  94.0:129.0Min:Max  64:249  45:250  45:250 Apo-A1 (mg/dL) Number 161 317 478 Mean(SD) 137.6 (27.2) 142.8 (27.4) 141.1 (27.4) Median   134.0   138.0  137.0 Q1:Q3 121.0:151.0 124.0:158.0 122.0:155.0 Min:Max  84:292 79:278  79:292 Apo-B/Apo-A1 (ratio) Number 161 317 478 Mean (SD)  0.859(0.292)  0.830 (0.269)  0.839 (0.277) Median     0.810     0.780    0.800 Q1:Q3 0.640:0.990 0.650:0.960 0.650:0.970 Min:Max 0.36:2.420.26:1.84 0.26:2.42 Total-C/HDL-C (ratio) Number 163 323 486 Mean (SD) 4.907 (1.838)  4.707 (1.756)  4.774 (1.785) Median     4.658     4.321    4.444 Q1:Q3 3.661:5.658 3.537:5.649 3.542:5.649 Min:Max  1.86:13.64 1.73:15.14  1.73:15.14 Note: Measured LDL-C was assessed via thebeta-quantification method.

The collection of measured LDL-C was not planned in the initial protocoland was added in an amendment. Therefore, measured LDL-C values areavailable for fewer patients compared to calculated LDL-C values.

Dosage and Duration

Exposure to injections was similar across treatment groups with a meanexposure of 59 weeks.

In the alirocumab group, among the 311 patients who received at leastone injection after Week 12, 135 (43.4%) patients received automaticup-titration from 75 mg Q2W to 150 mg Q2W at Week 12 in a blindedmanner.

Efficacy Primary Efficacy Endpoint

The ITT analysis includes all calculated LDL-C values collectedon-treatment and off-treatment up to Week 52. The primary endpoint(percent change in calculated LDL-C from baseline to Week 24) analysisis provided based on a MMRM model on the ITT population, using LS meansestimates at Week 24. Thirty-two (9.9%) patients in the alirocumab groupand 14 (8.6%) patients in the placebo group did not have a calculatedLDL-C value at Week 24. These missing values were accounted for by theMMRM model.

Results of the primary endpoint analysis are presented in Table 9, inmmol/L and mg/dL.

Primary Efficacy Analysis

A statistically significant decrease in percent change in LDL-C frombaseline to Week 24 was observed in the alirocumab group (LS mean versusbaseline−48.8%) compared to the placebo group (LS mean versusbaseline+9.1%) (LS mean difference vs. placebo of −57.9%, p<0.0001). Inthe alirocumab group, LDL-C reduction from baseline was observed fromWeek 4 and maintained throughout the study up to Week 78 (see FIG. 2 andTable 10).

TABLE 9 Percent change from baseline in calculated LDL-C at Week 24:MMRM - ITT analysis - ITT population Alirocumab 75 Calculated LDLPlacebo Q2W/Up150 Q2W Cholesterol (N = 163) (N = 322) Baseline (mmol/L)Number 163 322 Mean (SD) 3.739 (1.213)  3.748 (1.326) Median     3.574    3.497 Min:Max 1.71:9.17 1.01:9.95 Baseline (mg/dL) Number 163 322Mean (SD) 144.4 (46.8)   144.7 (51.2) Median   138.0   135.0 Min:Max 66:354  39:384 Week 24 percent change from baseline (%) LS Mean (SE)9.1 (2.2) −48.8 (1.6) LS mean difference (SE) −57.9 (2.7) vs placebo 95%CI (−63.3 to −52.6) p-value vs placebo     <0.0001* Note: Least-squares(LS) means, standard errors (SE) and p-value taken from MMRM(mixed-effect model with repeated measures) analysis. The model includesthe fixed categorical effects of treatment group, randomization strataas per IVRS, time point, treatment-by-time point and strata-by-timepoint interaction, as well as the continuous fixed covariates ofbaseline calculated LDL-C value and baseline calculated LDL-Cvalue-by-time point interaction MMRM model and baseline description runon patients with a baseline value and a post-baseline value in at leastone of the analysis windows used in the model. The p-value is followedby a ‘*’ if statistically significant according to the fixedhierarchical approach used to ensure a strong control of the overalltype-I error rate at the 0.05 level

TABLE 10 Calculated LDL-C over time - ITT analysis - ITT populationAlirocumab 75 Placebo Q2W/Up150 Q2W (N = 163) (N = 322) Percent PercentChange change Change change Calculated from from from from LDL-C Valuebaseline baseline Value baseline baseline LS Mean (SE) (mmol/L) Baseline^(a) 3.739 (0.095) NA NA 3.748 (0.074) NA NA Week 4 3.819 (0.070) 0.074(0.070) 4.3 (2.1) 1.996 (0.050) −1.749 (0.050) −46.7 (1.5) Week 8 3.805(0.073) 0.059 (0.073) 3.6 (1.8) 1.986 (0.052) −1.759 (0.052) −46.4 (1.3)Week 12 3.898 (0.074) 0.153 (0.074) 5.7 (2.0) 2.078 (0.053) −1.668(0.053) −43.5 (1.4) Week 16 3.892 (0.080) 0.147 (0.080) 5.6 (2.1) 1.763(0.057) −1.982 (0.057) −51.7 (1.5) Week 24 4.029 (0.084) 0.284 (0.084)9.1 (2.2) 1.846 (0.060) −1.899 (0.060) −48.8 (1.6) Week 36 3.965 (0.091)0.220 (0.091) 8.5 (2.4) 1.997 (0.066) −1.748 (0.066) −45.1 (1.8) Week 524.000 (0.092) 0.255 (0.092) 9.0 (2.6) 1.925 (0.066) −1.821 (0.066) −47.1(1.9) Week 64 3.947 (0.086) 1.962 (0.063) Week 78 4.082 (0.101) 2.177(0.073) LS Mean (SE) (mg/dL) Baseline ^(a) 144.4 (3.7) NA NA 144.7 (2.9)NA NA Week 4 147.5 (2.7) 2.9 (2.7) 4.3 (2.1) 77.1 (1.9) −67.5 (1.9)−46.7 (1.5) Week 8 146.9 (2.8) 2.3 (2.8) 3.6 (1.8) 76.7 (2.0) −67.9(2.0) −46.4 (1.3) Week 12 150.5 (2.9) 5.9 (2.9) 5.7 (2.0) 80.2 (2.0)−64.4 (2.0) −43.5 (1.4) Week 16 150.3 (3.1) 5.7 (3.1) 5.6 (2.1) 68.1(2.2) −76.5 (2.2) −51.7 (1.5) Week 24 155.6 (3.2) 11.0 (3.2) 9.1 (2.2)71.3 (2.3) −73.3 (2.3) −48.8 (1.6) Week 36 153.1 (3.5) 8.5 (3.5) 8.5(2.4) 77.1 (2.5) −67.5 (2.5) −45.1 (1.8) Week 52 154.4 (3.5) 9.8 (3.5)9.0 (2.6) 74.3 (2.6) −70.3 (2.6) −47.1 (1.9) Week 64 152.4 (3.3) 75.8(2.4) Week 78 157.6 (3.9) 84.0 (2.8) ^(a) Baseline is described usingmeans and standard errors. Note: Least-squares (LS) means, standarderrors (SE) and p-value taken from MMRM (mixed-effect model withrepeated measures) analysis. The model includes the fixed categoricaleffects of treatment group, randomization strata as per IVRS, timepoint, treatment-by-time point interaction, strata-by-time pointinteraction, as well as the continuous fixed covariates of baselineLDL-C value and baseline LDL-C value-by-time point interaction MMRMmodel and baseline description run on patients with a baseline value anda post-baseline value in at least one of the analysis windows used inthe model.

Key Secondary Efficacy Endpoints

Table 11 summarizes analysis results on key secondary endpoints in thehierarchical order. All key secondary endpoints are statisticallysignificant according to the hierarchical testing procedure.

TABLE 11 Endpoint Analysis Results P-value Calculated LDL-C - Percentchange On-treatment LS mean difference vs. <0.0001 from baseline to Week24 placebo of −58.1% Calculated LDL-C - Percent change ITT LS meandifference vs. <0.0001 from baseline to Week 12 placebo of −49.2%Calculated LDL-C - Percent change On-treatment LS mean difference vs.<0.0001 from baseline to Week 12 placebo of −49.5% Apo-B - Percentchange from ITT LS mean difference vs. <0.0001 baseline to Week 24placebo of −45.8% Apo-B - Percent change from On-treatment LS meandifference vs. <0.0001 baseline to Week 24 placebo of −45.9% Non-HDL-C -Percent change from ITT LS mean difference vs. <0.0001 baseline to Week24 placebo of −52.4% Non-HDL-C - Percent change from On-treatment LSmean difference vs. <0.0001 baseline to Week 24 placebo of −52.6%Total-C - Percent change from ITT LS mean difference vs. <0.0001baseline to Week 24 placebo of −38.7% Apo-B - Percent change from ITT LSmean difference vs. <0.0001 baseline to Week 12 placebo of −37.5%Non-HDL-C - Percent change from ITT LS mean difference vs. <0.0001baseline to Week 12 placebo of −43.7% Total-C - Percent change from ITTLS mean difference vs. <0.0001 baseline to Week 12 placebo of −32.5%Calculated LDL-C - Percent change ITT LS mean difference vs. <0.0001from baseline to Week 52 placebo of −56.2% Proportion of very high CVrisk ITT combined estimate for odds- <0.0001 patients reachingcalculated LDL- ratio vs. placebo of 155.1 C <70 mg/dL (1.81 mmol/L) orhigh CV risk patients reaching calculated LDL-C <100 mg/dL (2.59 mmol/L)at Week 24 Proportion of very high CV risk On-treatment combinedestimate for odds- <0.0001 patients reaching calculated LDL- ratio vs.placebo of 149.1 C <70 mg/dL (1.81 mmol/L) or high CV risk patientsreaching calculated LDL-C <100 mg/dL (2.59 mmol/L) at Week 24 Proportionof patients reaching ITT combined estimate for odds- <0.0001 calculatedLDL-C <70 mg/dL (1.81 ratio vs. placebo of 237.1 mmol/L) at Week 24Proportion of patients reaching On-treatment combined estimate for odds-<0.0001 calculated LDL-C <70 mg/dL (1.81 ratio vs. placebo of 237.9mmol/L) at Week 24 Lp(a) - Percent change from ITT combined estimate for<0.0001 baseline to Week 24 adjusted mean difference vs. placebo of−17.7% HDL-C - Percent change from ITT LS mean difference vs. <0.0001baseline to Week 24 placebo of 8% Fasting TGs - Percent change from ITTcombined estimate for <0.0001 baseline to Week 24 adjusted meandifference vs. placebo of −16.1% Apolipoprotein A1 - Percent change ITTLS mean difference vs. <0.05 from baseline to Week 24 placebo of 4.7%

The on-treatment analysis of LDL-C percent change from baseline to Week24 shows very consistent results with the ITT analysis (LS meandifference vs. placebo of −58.1% in the on-treatment analysis versus−57.9% in the ITT analysis). Indeed, few patients had LDL-C valuescollected post-treatment (i.e., more than 21 days after last injection)at Week 24: 6 patients (3.7%) in the placebo group and 2 patients (0.6%)in the alirocumab group. A statistically significant decrease in percentchange in LDL-C from baseline to Week 12 (i.e. before possibleup-titration) in the ITT analysis was observed in the alirocumab group(LS mean versus baseline−43.5%) compared to the placebo group (LS meanversus baseline+5.7%) (LS mean difference vs. placebo of −49.2%,p<0.0001).

The key secondary endpoints of Apo B, non-HDL-C, Total-C, Lp(a), HDL-C,and TGs at various time points as well as the proportion of patientsreaching their LDL-C goals and the proportion of patients reachingcalculated LDLD-C<70 mg/dL at Week 24 were statistically significantaccording to the hierarchical testing procedure. For the alirocumabgroup the baseline mean (SD) LDL-C, Non-LDL-C, ApoB and the median (IQR)Lp(a) levels were 144.7 (51.3), 170.3 (54.6), 114.3 (30.8), and 34(12:82) mg/dl respecticely. For the placebo group the baseline mean (SD)LDL-C, Non-LDL-C, ApoB and the median (IQR) Lp(a) levels were 144.4(46.8), 169.6 (50.6), 113.4 (28:5), and 23 (8.72)mg/dl respectively.After 24 weeks, LS mean (SE) % change from baseline to Week 24 forNon-LDL-C, ApoB Lp(a) levels in the alirocumab group was −42.8%, −41.1%,and −25.2%, respectively. The LS mean (SE) % change from baseline toWeek 24 for Non-LDL-C, ApoB Lp(a) levels for the placebo group was 9.6%,4.7%, and −7.5%, respectively. The LS mean difference vs. placebo forNon-LDL-C, ApoB and Lp(a) was −52.4%, −45.8%, and 17.7%, respectively.

The proportion of very high cardiovascular (CV) risk patients reachingcalculated LDL-C<70 mg/dL (1.81 mmol/L) or high CV risk patientsreaching calculated LDL-C<100 mg/dL (2.59 mmol/L) at Week 24 wassignificantly higher in the alirocumab than in the placebo group(combined estimate for proportion of 72.1% in the alirocumab group vs2.4% in the placebo group, p<0.0001).

Two consecutive calculated LDL-C values<25 mg/dL (<0.65 mmol/L) wereobserved in 16 (5.0%) patients. No particular safety concern has beenobserved in these patients.

TABLE 12 Number (%) of patients with 2 consecutive calculated LDL-C <25mg/dL (<0.65 mmol/L) during the treatment period- Safety populationAlirocumab 75 Placebo Q2W/Up150 Q2W (N = 163) (N = 322) Patients with 2consecutive calculated 0/163 16/317 (5.0%)   LDL-C value <25 mg/dL ¹Time to the first calculated LDL-C value <25 mg/dL (weeks) ² Number 016   Mean (SD) 14.79 (11.37) Median 14.14 Min:Max 3.1:36.1 Patients with2 consecutive calculated 0/163 6/317 (1.9%)  LDL-C value <15 mg/dL ¹Time to the first calculated LDL-C value <15 mg/dL (weeks) ² Number 06   Mean (SD) 18.31 (12.35) Median 20.14 Min:Max 4.6:36.1 The number (n)represents the subset of the total number of patients who met thecriteria The denominator (/N) within a treatment group is the number ofpatients for the treatment group who had at least two calculated LDL-Cvalues assessed at least 21 days apart in the efficacy period ¹ 2consecutive values are considered if spaced out by at least 21 days ²First calculated LDL-C value <25 or <15 mg/dL among the first 2consecutive calculated LDL-C values <25 or <15 mg/dL per patient

Summary Safety Results:

Alirocumab was well tolerated during the treatment period.

TABLE 13 Overview of adverse event profile: Treatment emergent adverseevents - Safety population Alirocumab 75 Placebo Q2W/Up150 Q2W n(%) (N =163) (N = 322) Patients with any TEAE 122 (74.8%) 249 (77.3%) Patientswith any treatment 15 (9.2%) 39 (12.1%) emergent SAE Patients with anyTEAE 0 4 (1.2%) leading to death Patients with any TEAE 8 (4.9%) 10(3.1%) leading to permanent treatment discontinuation n (%) = number andpercentage of patients with at least one TEAE

Overall, the proportions of patients reporting at least one treatmentemergent adverse event (TEAE) (77.3% in the alirocumab group and 74.8%in the placebo group) or at least one TEAE leading to permanentdiscontinuation (3.1% in the alirocumab group and 4.9% in the placebogroup) were similar in both groups. “Musculoskeletal and connectivetissue disorders” SOC was reported in 22.4% of patients in thealirocumab group vs. 25.2% in the placebo group. The most frequentlyreported TEAEs in both treatment groups were “injection site reaction”(11.8% vs. 9.8% in alirocumab vs. placebo group, respectively) and“nasopharyngitis” (9.9% vs 6.7% in alirocumab vs. placebo group,respectively). Among the events of interest, no particular signal wasdetected for TEAEs related to allergic events, neurological events,neurocognitive disorders and diabetes. The SOC “neoplasms begnin,malignant and unspecified” was observed in 2.8% of patients in thealirocumab group vs 0.6% in the placebo group with no particularclinical pattern on individual events (all these events were reported asnot related to IMP by the investigator). TEAEs “cardiovascular eventsconfirmed by adjudication” were reported for 1.9% of patients in thealirocumab group and 1.2% in the placebo group.

Six deaths (1.9%) were reported as not related to IMP by theinvestigator in the alirocumab group versus none in the placebo group:two myocardial infarctions (MI) (one classified as acute MI and oneclassified as sudden cardiac death), two metastatic cancers (non-smallcell lung cancer and pancreatic carcinoma with secondary Trousseausyndrome causing multiple embolic strokes), a colonic pseudo-obstructionfollowing abdominal surgery in one patient, and sudden cardiac death inone patient due to congestive cardiac failure and coronary arterydisease. Both patients with MI had multiple risk factors for coronaryartery disease. With regards to cancers, the time to onset of firstsymptoms (about 3.5 and 7.5 months after starting the investigationalproduct) is not suggestive of a causal role of the investigationalproduct.

No relevant abnormalities were observed for PCSA.

Example 3 A Randomized, Double-Blind, Placebo-Controlled, Parallel-GroupStudy to Evaluate the Efficacy and Safety of Alirocumab in Patients withHeterozygous Familial Hypercholesterolemia Not Adequately Controlledwith Their Lipid-Modifying Therapy Introduction

The objective of the study was to assess the efficacy and safety ofAlirocumab in improving lipid parameters in patients with heterozygousfamilial hypercholesterolemia (heFH) who have failed to reach theirLDL-C treatment goal on maximally-tolerated statin therapy, with orwithout additional lipid-modifying therapy (LMT). Patients not at goalon a maximally-tolerated dose of daily statin therapy, with or withoutother LMT, were enrolled in this study, and that their backgroundtreatment was maintained throughout the study.

This specific study (FIG. 3) was undertaken to demonstrate in heFHpatients who were not at their LDL-C goal, that Alirocumab 75 mg q2w or75 mg q2w/150 mg q2w as add-on therapy to statin+/−other LMT, causes astatistically significant and clinically meaningful reduction in LDL-C.This population that is not at LDL-C goal on optimized LMT represents ahighest risk group with a well-identified unmet medical need that can beaddressed by adding Alirocumab to their LDL-C lowering therapies.

Study Objectives

The primary objective of the study was to demonstrate the reduction ofLDL-C by Alirocumab as add-on therapy to stable, maximally-tolerateddaily statin therapy with or without other LMT in comparison withplacebo after 24 weeks of treatment in patients with heFH.

The secondary objectives of the study were: 1) to evaluate the effect ofAlirocumab 75 mg in comparison with placebo on LDL-C after 12 weeks oftreatment; 2) to evaluate the effect of Alirocumab on other lipidparameters (e.g., ApoB, non-HDL-C, total-C, Lp[a], HDL-C, TG levels, andApoA-1 levels); 3) to evaluate the long-term effect of Alirocumab onLDL-C; 4) to evaluate the safety and tolerability of Alirocumab; and 5)to evaluate the development of anti-Alirocumab antibodies.

Study Design

This was a randomized, double-blind, placebo-controlled, parallel-group,multi-national study in patients with heFH who were not adequatelycontrolled with their LMT (i.e., stable maximally-tolerated daily statintherapy+/−other LMT). Not adequately controlled was defined as anLDL-C≥70 mg/dL (1.81 mmol/L) at the screening visit (week 2) in patientswith a history of documented CVD or LDL-C≥100 mg/dL (2.59 mmol/L) at thescreening visit (week-2) in patients without a history of documentedCVD. Patients were randomized in a 2:1 ratio to receive either 75 mg ofAlirocumab or placebo by SC injection, every 2 weeks, on top of stable,maximally-tolerated daily statin therapy (atorvastatin, rosuvastatin, orsimvastatin) with or without other LMT. Randomization was stratifiedaccording to prior history of either myocardial infarction (MI) orischemic stroke, and statin treatment (atorvastatin 40 mg to 80 mg dailyor rosuvastatin 20 mg to 40 mg daily vs. simvastatin whatever the dailydose, atorvastatin below 40 mg daily, or rosuvastatin below 20 mgdaily).

The study consisted of three periods: a screening period, a treatmentperiod, and a follow-up period.

The screening period was up to 2 weeks, including an intermediate visitduring which the patient or caregiver was trained to self-inject/injectusing a dose of placebo.

The double-blind treatment period was 78 weeks. The first injection ofstudy drug was administered at the clinical site on day 1, after studyassessments were completed, and as soon as possible after the patientwas randomized into the study. The patient/caregiver administeredsubsequent injections outside of the clinic according to the dosingschedule. On days where the clinic study visit coincides with dosing,the dose of study drug was administered after all study assessments wereperformed and all laboratory samples collected. The last dose of studydrug was administered at week 76. At week 12, patients randomized toAlirocumab were, in a blinded manner, either: 1) continued Alirocumab 75mg every 2 weeks, if the week 8 LDL-C was <70 mg/dL (1.81 mmol/L), or 2)dose up-titrated to Alirocumab 150 mg every 2 weeks, if the week 8 LDL-Cwas ≥70 mg/dL (1.81 mmol/L).

The follow-up period (if applicable) was 8 weeks after the end of theDBTP for patients not consenting to participate in the open-labelextension study, or if prematurely discontinuing study treatment.

Patients were asked to follow a stable diet (equivalent to the NationalCholesterol Education Program Adult Treatment Panel Ill TherapeuticLifestyle Changes [NCEP ATP III TLC] diet/Appendix 5) from screening tothe end of study visit. The daily dose of statin or other LMT (ifapplicable) should remain stable from screening to the end of studyvisit. Starting at week 24, background LMT may be modified under certainconditions as described later. Table 1 from Example 2 is relevant tothis Example and provides a summary of the TLC diet for highcholesterol.

An independent external physician was notified by the central laboratoryfor any patient who achieved 2 consecutive calculated LDL-C levels<25mg/dL (0.65 mmol/L). Patients who meet this criterion were monitored.

Selection of Patients

The study population consisted of patients with heFH who were notadequately controlled with a maximally-tolerated stable daily dose of astatin for at least 4 weeks before the screening visit (week-2), with orwithout other LMT.

A patient must have met the following criteria to be eligible forinclusion in the study: 1) patients with heFH* who were not adequatelycontrolled** with a maximally-tolerated daily dose*** of statin with orwithout other LMT, at a stable dose prior to the screening visit(week-2).

*Diagnosis of heFH must be made either by genotyping or by clinicalcriteria. For those patients not genotyped, the clinical diagnosis maybe based on either the Simon Broome criteria for definite FH or theWHO/Dutch Lipid Network criteria with a score of >8 points.

Definite familial hypercholesterolemia was defined herein the same as itwas in Example 2. Possible familial hypercholesterolemia was definedherein the same as it was in Example 2. The WHO Criteria (Dutch LipidNetwork clinical criteria) for Diagnosis of Heterozygous FamilialHypercholesterolemia (heFH) set forth in Table 2 in Example 2 was thesame for this Example.

**“Not adequately controlled” was defined herein the same as it was inExample 2.

A Documented History of CHD was defined herein the same as in Example 2.

CHD Risk Equivalents (includes 1 or more of the following criteria): 1)documented peripheral arterial disease (one of the following criteriamust be satisfied): A) current intermittent claudication (musclediscomfort in the lower limb produced by exercise that is bothreproducible and relieved by rest within 10 minutes) of presumedatherosclerotic origin together with ankle-brachial index equal to orless than 0.90 in either leg at rest, or B) history of intermittentclaudication (muscle discomfort in the lower limb produced by exercisethat is both reproducible and relieved by rest within 10 minutes)together with endovascular procedure or surgical intervention in one orboth legs because of atherosclerotic disease, or C) history of criticallimb ischemia together with thrombolysis, endovascular procedure orsurgical intervention in one or both legs because of atheroscleroticdisease; 2) documented previous ischemic stroke with a focal ischemicneurological deficit that persisted more than 24 hours, considered asbeing of atherothrombotic origin. CT or MRI must have been performed torule out hemorrhage and non-ischemic neurological disease.

***“Maximally-tolerated dose” was defined herein the same as it was inExample 2.

Patients who met all of the above inclusion criteria were screened forthe following exclusion criteria, which are sorted in the followingthree subsections: exclusion criteria related to study methodology,exclusion criteria related to the active comparator and/or mandatorybackground therapies, and exclusion criteria related to the currentknowledge of Alirocumab.

Exclusion criteria related to the study methodology were: 1) patientwithout diagnosis of heFH made either by genotyping or by clinicalcriteria; 2) LDL-C<70 mg/dL (<1.81 mmol/L) at the screening visit(week-2) in patients with history of documented CVD. NOTE: CVD isdefined as CHD, ischemic stroke, or peripheral arterial disease asdescribed above; 3) LDL-C<100 mg/dL (<2.59 mmol/L) at the screeningvisit (week-2) in patients without history of documented CVD; 4) not ona stable dose of LMT (including statin) for at least 4 weeks and/orfenofibrate for at least 6 weeks, as applicable, prior to the screeningvisit (week-2) and from screening to randomization; 5) currently takinganother statin than simvastatin, atorvastatin, or rosuvastatin; 6)simvastatin, atorvastatin, or rosuvastatin is not taken daily or nottaken at a registered dose; 7) daily doses above atorvastatin 80 mg,rosuvastatin 40 mg, or simvastatin 40 mg (except for patients onsimvastatin 80 mg for more than 1 year, who are eligible); 8) use offibrates, other than fenofibrate within 6 weeks of the screening visit(week-2) or between screening and randomization visits; 9) use ofnutraceutical products or over-the-counter therapies that may affectlipids which have not been at a stable dose/amount for at least 4 weeksprior to the screening visit (week-2) or between screening andrandomization visits; 10) use of red yeast rice products within 4 weeksof the screening visit (week-2), or between screening and randomizationvisits; 11) patient who has received plasmapheresis treatment within 2months prior to the screening visit (week-2), or has plans to receive itduring the study; 12) recent (within 3 months prior to the screeningvisit [week-2] or between screening and randomization visits) MI,unstable angina leading to hospitalization, percutaneous coronaryintervention (PCI), coronary artery bypass graft surgery (CABG),uncontrolled cardiac arrhythmia, stroke, transient ischemic attack,carotid revascularization, endovascular procedure or surgicalintervention for peripheral vascular disease; 13) planned to undergoscheduled PCI, CABG, carotid, or peripheral revascularization during thestudy; 14) systolic blood pressure>160 mm Hg or diastolic bloodpressure>100 mm Hg at screening visit or randomization visit; 15)history of New York Heart Association (NYHA) Class III or IV heartfailure within the past 12 months; 16) known history of a hemorrhagicstroke; 17) age<18 years or legal age of majority at the screening visit(week-2), whichever is greater; 18) patients not previously instructedon a cholesterol-lowering diet prior to the screening visit (week-2);19) newly diagnosed (within 3 calendar months prior to randomizationvisit [week 0]) or poorly controlled (hemoglobin A1c [HbA1c]>9% at thescreening visit [week-2]) diabetes; 20) presence of any clinicallysignificant uncontrolled endocrine disease known to influence serumlipids or lipoproteins. Note: Patients on thyroid replacement therapycan be included if the dosage has been stable for at least 12 weeksprior to screening and between screening and randomization visits, andthyroid-stimulating hormone (TSH) level is within the normal range ofthe central laboratory at the screening visit; 21) history of bariatricsurgery within 12 months prior to the screening visit (week −2); 22)unstable weight defined by a variation>5 kg within 2 months prior to thescreening visit (week-2); 23) known history of homozygous FH; 24) knownhistory of loss-of-function of PCSK9 (ie, genetic mutation or sequencevariation); 25) use of systemic corticosteroids, unless used asreplacement therapy for pituitary/adrenal disease with a stable regimenfor at least 6 weeks prior to randomization visit (week 0). Note:Topical, intra-articular, nasal, inhaled and ophthalmic steroidtherapies are not considered as ‘systemic’ and are allowed; 26) use ofcontinuous estrogen or testosterone hormone replacement therapy unlessthe regimen has been stable in the past 6 weeks prior to the screeningvisit (week-2) and no plans to change the regimen during the study; 27)history of cancer within the past 5 years, except for adequately treatedbasal cell skin cancer, squamous cell skin cancer, or in situ cervicalcancer; 28) known history of a positive HIV test; 29) patient who hastaken any investigational drugs other than the Alirocumab trainingplacebo kits within 1 month or 5 half-lives, whichever is longer; 30)patient who has been previously treated with at least 1 dose ofAlirocumab or any other anti-PCSK9 monoclonal antibody in other clinicalstudies; 31) conditions/situations such as: a) any clinicallysignificant abnormality identified at the time of screening that, in thejudgment of the investigator or any sub-investigator, would precludesafe completion of the study or constrain endpoints assessment; eg,major systemic diseases, patients with short life expectancy; or b)considered by the investigator or any sub-investigator as inappropriatefor this study for any reason, e.g.: i) deemed unable to meet specificprotocol requirements, such as scheduled visits; ii) those deemed unableto administer or tolerate long-term injections as per the patient or theinvestigator; iii) investigator or any sub-investigator, pharmacist,study coordinator, other study staff or relative thereof directlyinvolved in the conduct of the protocol, etc.; iv) presence of any otherconditions (eg, geographic or social), either actual or anticipated,that the investigator feels would; 32) laboratory findings duringscreening period (not including randomization week 0 labs, unlessotherwise noted): i) positive test for hepatitis B surface antigen orhepatitis C antibody (confirmed by reflexive testing); ii) positiveserum beta-hCG or urine pregnancy test (including week 0) in women ofchildbearing potential; iii) TG>400 mg/dL (>4.52 mmol/L) (1 repeat labis allowed); iv) eGFR<30 mL/min/1.73 m2 according to 4-variable MDRDstudy equation (calculated by central lab); v) alanine aminotransferase(ALT) or aspartate aminotransferase (AST)>3×upper limit of normal (ULN)(1 repeat lab is allowed); vi) CPK>3×ULN (1 repeat lab is allowed); vii)TSH<lower limit of normal (LLN) or >ULN (1 repeat lab is allowed).

Exclusion criteria related to the active comparator and/or mandatorybackground therapies were: 1) all contraindications to the backgroundtherapies or warnings/precautions of use (when appropriate) as displayedin the respective National Product Labeling.

Exclusion criteria related to the current knowledge of Alirocumabwere: 1) known hypersensitivity to monoclonal antibody or any componentof the drug product; 2) pregnant or breast-feeding women; 3) women ofchildbearing potential who are not protected by highly-effectivemethod(s) of birth control (as defined in the informed consent formand/or in a local protocol addendum) and/or who are unwilling or unableto be tested for pregnancy. Note: Women of childbearing potential musthave a confirmed negative pregnancy test at screening and randomizationvisits. They must use an effective contraceptive method throughout theentire duration of study treatment and for 10 weeks after the last doseof study drug, and agree to repeat urine pregnancy test at designatedvisits. The applied methods of contraception have to meet the criteriafor a highly effective method of birth control according to the “Notefor guidance on non-clinical safety studies for the conduct of humanclinical trials for pharmaceuticals (CPMP/ICH/286/95)”. Postmenopausalwomen must be amenorrheic for at least 12 months.

Study Treatments

The study treatment was a single SC injection of 1 mL for a 75 mg or 150mg dose of Alirocumab or placebo provided in an auto-injector,administered in the abdomen, thigh, or outer area of the upper arm. Thefirst injection of study drug was administered at the clinical site, assoon as possible after the patient was randomized into the study. Thepatient was monitored at the clinical site for 30 minutes following thefirst injection. The patient/caregiver administered subsequentinjections outside of the clinic, according to the dosing schedule. Ondays where the clinic study visit coincided with dosing, the dose ofstudy drug was administered after all study assessments were performedand all laboratory samples collected. Subcutaneous dosing of study drugshould be administered every 2 weeks at approximately the same time ofday (based upon patient preference); it was acceptable for dosing tofall within a window of +/−3 days.

Sterile Alirocumab drug product was supplied at a concentration of 75mg/mL or 150 mg/mL in histidine, pH 6.0, polysorbate 20, and sucrose inan auto-injector.

Placebo matching Alirocumab was supplied in the same formulation asAlirocumab, without the addition of protein, in an auto-injector.

All patients were on a maximally-tolerated stable daily statin(atorvastatin, rosuvastatin, or simvastatin)+/−other LMT throughout theduration of the study. Statin dose and the dose of other LMT (ifapplicable) should have remained stable throughout the whole studyduration, from screening to the end of study visit.

During the double-blind treatment period, modification to the backgroundLMT was allowed before week 24 only under certain conditions: 1)exceptional circumstances—overriding concerns (including, but notlimited to, TG alert, below, posted by the central lab) warrant suchchanges, per the investigator's judgment; or 2) a confirmed TG alert—thepatient meets the pre-specified TG alert (TG ≥500 mg/dL [5.65 mmol/L]).

During the double-blind treatment period, modification to the backgroundLMT was allowed after week 24 only under certain conditions: 1)exceptional circumstances, per the investigator's judgment; 2) aconfirmed TG alert—the patient meets the pre-specified TG alert (TG 500mg/dL [5.65 mmol/L], or 3) LDL-C increased by at least 25% as comparedto the randomization visit LDL-C (and no other reasonable explanationexists).

For a laboratory rescue alert of LDL-C increase>25% as compared to therandomization visit LDL-C on 2 consecutive occasions, the investigatorshould have ensured that no reasonable explanation exists forinsufficient LDL-C control (such as an alternative medical cause likecorticosteroid use, etc.) and in particular that: compliance with dietwas appropriate; compliance with background LMT was appropriate; andstudy treatment was given as planned. If any of the above couldreasonably explain the insufficient LDL-C control, the investigatorshould have stressed the absolute need to be compliant with treatmentand, if needed, organized a specific interview with a qualifiednutrition professional and stressed the absolute need to be compliantwith diet, and performed a blinded LDL-C assessment within 1 to 2months. Rescue treatment may be initiated in the event that no reasonfor LDL-C above the threshold value could be found.

If no reason for LDL-C above the threshold value could be found, or ifappropriate action failed to decrease LDL-C below the threshold value,rescue medication may have been introduced. The effectiveness of anysuch changes would be made based on lack of rescue threshold fromblinded lipid testing at the next routinely scheduled lab draw. Patientsper protocol already received a maximum tolerated dose of statin, sostatin up-titration or switch would not be an option. For further LDL-Clowering, the investigator may have considered adding: a cholesterolabsorption inhibitor (ezetimibe), or a bile acid-binding sequestrant(the resins cholestyramine and colestipol, or colesevelam, anonabsorbable polymer). The following lipid modifying agents may havealso been considered: fibrate (Note: Caution should be exercised whencombining fibrates with other cholesterol-lowering medications such asstatins because of the risk of myopathy. When a fibrate is combined witha statin, fenofibrate is the fibrate of choice because it does notaffect statin glucuronidation. The only fibrate allowed per protocol wasfenofibrate); nicotinic acid (niacin) (Note: Niacin raises blood glucosebut has been shown to be effective in modifying lipid disorders inpeople with diabetes if glucose control is maintained).

The dose of study drug was increased (up-titrated) from 75 mg to 150 mgSC every 2 weeks, starting at week 12, for an individual patient in theevent LDL-C≥70 mg/dL at the week 8 visit.

Patients were randomized to receive either Alirocumab or placebo in aratio of 2:1, with permuted-block randomization. Randomization wasstratified according to prior history of MI or ischemic stroke (Yes/No),and statin dose (“Yes” as atorvastatin 40 mg to 80 mg daily orrosuvastatin 20 mg to 40 mg daily and “No” as simvastatin whatever thedaily dose, atorvastatin below 40 mg daily or rosuvastatin below 20 mgdaily) as fixed effects; and the baseline calculated LDL-C as covariate.

Concomitant medications should have been kept to a minimum during thestudy. If considered necessary for the patient's welfare and unlikely tointerfere with study drug, concomitant medications (other than thosethat are prohibited during the study) could have been given at thediscretion of the investigator, with a stable dose (when possible).

Nutraceutical products or over-the-counter therapies that may affectlipids were allowed only if they had been used at a stable dose for atleast 4 weeks before the screening visit, during the screening period,and maintained during the first 24 weeks of the double-blind treatmentperiod. After the week 24 visit, modification to these nutraceuticalproducts or over-the-counter therapies was allowed, but in generalshould have been avoided. Examples of such nutraceutical products orover-the-counter therapies include omega-3 fatty acids at doses<1000 mg,plant stanols such as found in Benecol, flax seed oil, and psyllium.

Women of childbearing potential must have used an effectivecontraception method throughout study treatment, and for 10 weeks afterthe last dose of study drug.

Prohibited concomitant medications from the initial screening visituntil the end of the study visit included the following: statins, otherthan atorvastatin, rosuvastatin, or simvastatin; fibrates, other thanfenofibrate; and red yeast rice products.

Study Endpoints

Baseline characteristics included standard demography (e.g., age, race,weight, height, etc.), disease characteristics including medicalhistory, and medication history for each patient.

The primary efficacy endpoint was the percent change in calculated LDL-Cfrom baseline to week 24, which was defined as: 100×(calculated LDL-Cvalue at week 24-calculated LDL-C value at baseline)/calculated LDL-Cvalue at baseline. The baseline calculated LDL-C value was the lastLDL-C level obtained before the first dose of study drug. The calculatedLDL-C at week 24 was the LDL-C level obtained within the week 24analysis window and during the main efficacy period. The main efficacyperiod was defined as the time from the first double-blind study druginjection up to 21 days after the last double-blind study drug injectionor up to the upper limit of the week 24 analysis window, whichever camefirst.

The key secondary efficacy endpoints were: 1) the percent change incalculated LDL-C from baseline to week 12: similar definition and rulesas for primary efficacy endpoint, except that the calculated LDL-C atweek 12 was the LDL-C level obtained within the week 12 analysis windowand during the 12-week efficacy period. The 12-week efficacy period wasdefined as the time from the first double-blind study drug injection upto the visit 6 re-supply IVRS contact or up to 21 days after the laststudy drug injection, whichever came first. Blood sampling collected theday of the visit 6 re-supply IVRS contact will be considered as beforetitration; 2) the percent change in ApoB from baseline to week 24. Samedefinition and rules as for the primary endpoint; 3) the percent changein non-HDL-C from baseline to week 24. Same definition and rules as forthe primary endpoint; 4) the percent change in total-C from baseline toweek 24. Same definition and rules as for the primary endpoint; 5) thepercent change in ApoB from baseline to week 12. Same definition andrules as for the percent change in calculated LDL-C from baseline toweek 12; 6) the percent change in non-HDL-C from baseline to week 12.Same definition and rules as for the percent change in calculated LDL-Cfrom baseline to week 12; 7) the percent change in total-C from baselineto week 12. Same definition and rules as for the percent change incalculated LDL-C from baseline to week 12; 8) the percent change incalculated LDL-C from baseline to week 52. Definitions and rules aresimilar to the ones used for the primary endpoint replacing week 24 byweek 52; 9) the proportion of patients reaching LDL-C goal at week 24,i.e., LDL-C<70 mg/dL (1.81 mmol/L) in case of prior CVD or <100 mg/dL(2.59 mmol/L) for patients without prior CVD, defined as: (number ofpatients whose calculated LDL-C value at week 24 reach LDL-C goal/numberof patients in the [modified intent-to-treat (mITT population)]*100,using definition and rules used for the primary endpoint; 10) theproportion of patients reaching LDL-C<70 mg/dL (1.81 mmol/L) at week 24;11) the percent change in Lp(a) from baseline to week 24. Samedefinition and rules as for the primary endpoint; 12) the percent changein HDL-C from baseline to week 24. Same definition and rules as for theprimary endpoint; 13) the percent change in HDL-C from baseline to week12. Same definition and rules as for the percent change in calculatedLDL-C from baseline to week 12; 14) the percent change in Lp(a) frombaseline to week 12. Same definition and rules as for the percent changein calculated LDL-C from baseline to week 12; 15) the percent change infasting TG from baseline to week 24. Same definition and rules as forthe primary endpoint; 16) the percent change in fasting TG from baselineto week 12. Same definition and rules as for the percent change incalculated LDL-C from baseline to week 12; 17) the percent change inApoA-1 from baseline to week 24. Same definition and rules as for theprimary endpoint; 18) the percent change in ApoA-1 from baseline to week12. Same definition and rules as for the percent change in calculatedLDL-C from baseline to week 12.

Other secondary efficacy endpoints were: 1) the percent change incalculated LDL-C from baseline to week 78. Definitions and rules aresimilar to the ones used for the primary endpoint replacing week 24 byweek 78; 2) the proportion of patients reaching LDL-C goal at weeks 12,52, and 78, i.e., LDL-C<70 mg/dL (1.81 mmol/L) in case of prior CVD or<100 mg/dL (2.59 mmol/L) for patients without prior CVD; 3) theproportion of patients reaching LDL-C<100 mg/dL (2.59 mmol/L) at week24; 4) the proportion of patients reaching LDL-C<100 mg/dL (2.59 mmol/L)at week 12; 5) the proportion of patients reaching LDL-C<70 mg/dL (1.81mmol/L) at week 12; 6) the absolute change in calculated LDL-C (mg/dLand mmol/L) from baseline to weeks 12, 24, 52, and 78; 7) the percentchange in ApoB, non-HDL-C, total-C, Lp(a), HDL-C, fasting TG, and ApoA-1from baseline to weeks 52 and 78; 8) the change in ratio ApoB/ApoA-1from baseline to weeks 12, 24, 52, and 78; 9) the proportion of patientswith ApoB<80 mg/dL (0.8 g/L) at weeks 12, 24, 52, and 78; 10) theproportion of patients with non-HDL-C<100 mg/dL at weeks 12, 24, 52, and78; 11) the proportion of patients with calculated LDL-C<70 mg/dL (1.81mmol/L) and/or ≥50% reduction in calculated LDL-C (if calculatedLDL-C≥70 mg/dL [1.81 mmol/L]) at weeks 12, 24, 52, and 78.

Other endpoints were: 1) anti-Alirocumab antibody status(positive/negative) and titers assessed throughout the study; 2) thepercent change in high sensitivity C-reactive protein (hs-CRP) frombaseline to weeks 24, 52, and 78; 3) the absolute change in HbA1c (%)from baseline to weeks 24, 52, and 78; and 4) response of each EQ-5Ditem, index score, and change of index score from baseline through week52.

Study Visits

The following visits were scheduled:

At Visit 1/Screening/Day −14 to −8; Visit 2/Screening/Day −7 (+/−3days); Visit 3/Baseline/Week 0/Day 1; Visit 4/Week 4/Day 29 (+/−7 days);Visit 6/Week 12/Day 85 (+/−3 days); Visit 7/Week 16/Day 113 (+/−7 days);Visit 8/Week 24/Day 169 (+/−3 days)/Primary Endpoint Assessment; Visit9/Week 36/Day 253 (+/−7 days); Visit 10/Week 52/Day 365 (+/−5 days);Visit 11/Week 64/Day 449 (+/−7 days); Visit 12/Week 78/Day 547 (+/−5days); and the End of Study/Visit 13/Week 86/Day 603 (+/−7 days).

Medical/surgical history, medication history, demographics, height,hepatitis B surface antigen, and serum pregnancy testing were performedfor the purpose of determining study eligibility or characterizing thebaseline population.

All laboratory samples were collected before the dose of study drug wasadministered.

Blood samples for lipid panels should be collected in the morning, infasting condition (i.e., overnight at least 10 hours fast, only water,and refrain from smoking) for all clinic visits. Alcohol consumptionwithin 48 hours, and intense physical exercise and smoking within 24hours preceding blood sampling were discouraged. Note: if the patientwas not in fasting condition, the lipid blood samples were collected anda new appointment was scheduled the day after (or as close as possibleto this date), with a reminder for the patient to be fasted.

Sample Size and Power Considerations

A total sample size of 45 patients (30 in alirocumab and 15 in placebo)will have 95% power to detect a difference in mean percent change inLDL-C of 30% with a 0.05 two-sided significance level; assuming a commonstandard deviation of 25% and that all 45 patients have an evaluableprimary endpoint.

To meet regulatory requirements across the program, the sample size wasincreased to 126 patients on alirocumab, with the intent to understandsafety in a larger population. In order to have at least 126 patients onalirocumab treated for 12 months in this study, and assuming a drop-outrate of 10% over the first 3-month period and a drop-out rate of 20%over the remaining 9-month period, the final total sample size wasincreased and rounded to 250 patients, with a randomization ratio 2:1(alirocumab: 167, placebo: 83).

Analysis Populations Intent-to-Treat Population

The randomized population included all randomized patients, and wasanalyzed according to the treatment allocated by randomization.

The ITT population (also known as the full analysis set [FAS]) wasdefined as all randomized patients who had an evaluable primaryendpoint. The endpoint was evaluable when the following two conditionswere met: 1) availability of a baseline calculated LDL-C value; and 2)availability of at least 1 calculated LDL-C value within 1 of theanalysis windows up to week 24.

Patients in the ITT population were analyzed according to the treatmentgroup allocated by randomization (i.e., as-randomized treatment group).

Modified Intent-to-Treat

The mITT population was defined as the all randomized population whotook at least 1 dose or part of a dose of study drug and had anevaluable primary endpoint. The endpoint was considered as evaluable(i.e. efficacy treatment period) when both of the following conditionswere met: 1) availability of a baseline calculated LDL-C value; and 2)availability of at least 1 calculated LDL-C value during the efficacytreatment period and within one of the analysis windows up to week 24.The efficacy treatment period is defined as the time from the firstdouble-blind study drug injection up to 21 days after the lastdouble-blind study drug injection.

Patients in the mITT population were analyzed according to the treatmentgroup allocated by randomization.

Safety Analysis Set

The safety population considered for safety analyses was the randomizedpopulation who received at least 1 dose or part of a dose of study drug.Patients were analyzed according to the treatment actually received(i.e. as-treated treatment group, placebo or alirocumab).

Results Description of Study Populations

A total of 249 patients were randomized (82 to the placebo group and 167to the alirocumab group) in this study. One patient in the placebo groupwas randomized but did not receive study treatment due to the reason ofwithdrew consent prior to receiving the first IMP injection. Therefore,the patient was excluded from the safety population. Two patients amongthe randomized patients (the one in the placebo group above and one inthe alirocumab group) were excluded from the ITT and mITT populationsdue to lack of post-baseline LDL-C assessments.

TABLE 14 Analysis Populations Alirocumab 75 Placebo Q2W/Up150 Q2W All (N= 82) (N = 167) (N = 249) Randomized 82 (100%)  167 (100%)  249 (100%) population Efficacy population: Intent-to-Treat (ITT) 81 (98.8%) 166(99.4%) 247 (99.2%) Modified Intent-to- 81 (98.8%) 166 (99.4%) 247(99.2%) Treat (mITT) Quality-of-life 80 (97.6%) 164 (98.2%) 244 (98.0%)population Anti-alirocumab 77 (93.9%) 166 (99.4%) 243 (97.6%) antibodypopulation Safety population 81 (98.8%) 167 (100%)  248 (99.6%) Note:The safety, and anti-alirocumab antibody population patients aretabulated according to treatment actually received (as treated). For theother populations, patients are tabulated according to their randomizedtreatment

In the alirocumab group, among the 158 patients who received at leastone injection after Week 12, 61 (38.6%) patients received automaticup-titration at Week 12 in a blinded manner from alirocumab 75 mg Q2W to150 mg Q2W.

Subject Dispositions

As of the first-step analyses data cut-off date, patient status ispresented below for the 249 randomized patients: 1) 0 (0.0%) patientscompleted the 78-week double-blind treatment period, due to ongoingpatients not yet reaching the week 78 visit; 2) 234 (94.0%) patientswere still treatment-ongoing: 78 (95.1%) in the placebo group and 156(93.4%) in the alirocumab group; 3) 9 (3.6%) randomized and treatedpatients prematurely discontinued study treatments before Week 24: 1(1.2%) in the placebo group and 8 (4.8%) in the alirocumab group. 4(1.6%) patients prematurely terminated study treatments due to adverseevents: 0 in the placebo group vs. 4 (2.4%) in the alirocumab group. 3(1.2%) patients prematurely terminated study treatments due to poorprotocol compliance: 1 (1.2%) in the placebo group and 2 (1.2%) in thealirocumab group. 2 (0.8%) patients prematurely terminated studytreatments due to various other reasons: 0 in the placebo group vs. 2(1.2%) in the alirocumab group; 4) 13 (5.2%) randomized and treatedpatients prematurely discontinued study treatments before Week 52: 2(2.4%) in the placebo group and 11 (6.6%) in the alirocumab group. 5(2.0%) patients prematurely terminated study treatments due to adverseevents: 0 in the placebo group vs. 5 (3.0%) in the alirocumab group. 3(1.2%) patients prematurely terminated study treatments due to poorprotocol compliance: 1 (1.2%) in the placebo group and 2 (1.2%) in thealirocumab group. 5 (0.8%) patients prematurely terminated studytreatments due to various other reasons: 1 (1.2%) in the placebo groupand 4 (2.4%) in the alirocumab group; 5) 14 (5.6%) patients prematurelyterminated study treatments before completing the 78-week treatmentperiod: 3 (3.7%) in the placebo group and 11 (6.6%) in the alirocumabgroup. 6 (2.4%) patients prematurely terminated study treatments due toadverse events: 1 (1.2%) in the placebo group and 5 (3.0%) in thealirocumab group. 3 (1.2%) patients prematurely terminated studytreatments due to poor protocol compliance: 1 (1.2%) in the placebogroup and 2 (1.2%) in the alirocumab group. 5 (2.0%) patientsprematurely terminated study treatments due to various other reasons: 1(1.2%) in the placebo group and 4 (2.4%) in the alirocumab group.

The following table provides the availability of LDL-C values over time.At Week 24, the primary efficacy endpoint was available for 78 (96.3%)patients in the placebo group and 157 (94.5%) in the alirocumab group.There were 77 (95.1%) on-treatment assessments and 1 (1.2%)off-treatment assessments in the placebo group, as compared with 155(93.4%) on-treatment assessments and 2 (1.2%) off-treatment assessmentsin the alirocumab group. At Week 52, the key secondary efficacy endpointwas available for 78 (96.3%) patients in the placebo and 158 (95.2%)patients in the alirocumab groups.

TABLE 15 Calculated LDL-C Availability over Time - ITT PopulationAlirocumab 75 Placebo Q2W/Up150 Q2W (N = 81) (N = 166) On- Post- On-Post- Calculated treatment treatment Missing treatment treatment MissingLDL-C value value value value value value WEEK 4 79 (97.5%) 0 2 (2.5%)162 (97.6%) 0 4 (2.4%) WEEK 8 79 (97.5%) 0 2 (2.5%) 156 (94.0%) 0 10(6.0%) WEEK 12 76 (93.8%) 0 5 (6.2%) 151 (91.0%) 1 (0.6%) 14 (8.4%) WEEK16 77 (95.1%) 0 4 (4.9%) 149 (89.8%) 3 (1.8%) 14 (8.4%) WEEK 24 77(95.1%) 1 (1.2%) 3 (3.7%) 155 (93.4%) 2 (1.2%) 9 (5.4%) WEEK 36 73(90.1%) 0 8 (9.9%) 153 (92.2%) 2 (1.2%) 11 (6.6%) WEEK 52 78 (96.3%) 0 3(3.7%) 155 (93.4%) 3 (1.8%) 8 (4.8%) An on-treatment value was obtainedafter the first study treatment injection and within 21 days after thelast study treatment injection. A post-treatment value was obtained morethan 21 deays after the last study treatment injection.

The primary endpoint was missing for 12 (4.9%) patients at Week 24. Atthe Week 24 visit, the reasons for missing values were as follows: 1) 4subjects with samples not obtained due to earlier study discontinuation;2) 2 subjects were still ongoing, but Week 24 LDL-C was not done; 3) 6samples were obtained at Week 24, but the LDL-C could not be calculated(5 with TGs>400 mg/dL and measured LDL-C reported, 1 with >400 mg/dL butmeasured LDL-C not reported).

Demographic and Baseline Characteristics

Overall, demographic characteristics, baseline disease characteristics,baseline efficacy lipid parameters, LMT history and background LMT usewere homogeneous between patients randomized to the alirocumab group andpatients randomized to the placebo group (see Table 16). Particularly,the mean baseline LDL-C in the alirocumab group was 134.6 mg/dL (SD=41.1mg/dL) compared to that in the placebo group being 134.0 mg/dL (SD=41.4mg/dL) with an overall mean of 134.4 mg/dL (SD=41.1 mg/dL). Onepotentially notable exception is the difference observed in baselineBMI, with a mean BMI of 28.6 kg/m2 (SD=4.6 kg/m2) in the alirocumabgroup compared to 27.7 kg/m2 (SD=4.7 kg/m2) in the placebo group.

TABLE 16 Baseline Characteristics of FHII Patient Population AlirocumabPlacebo Characteristic (N = 167) (N = 82) Age, mean (SD), yrs 53.2(12.9) 53.2 (12.5) Diagnosis of heFH^(†), % (n) Genotyping 70.1% (117)81.7% (67) Clinical criteria 29.9% (50) 18.3% (15) Male 51.5% (86) 54.9%(45) Race, white 98.2% (164) 97.6% (80) BMI, mean (SD), kg/m² 28.6 (4.6)27.7 (4.7) CHD history 34.1% (57) 37.8% (31) CHD risk equivalents^(†)9.0% (15) 4.9% (4) Current smoker 21.6% (36) 15.9% (13) Hypertension34.1% (57) 29.3% (24) Type 2 diabetes 4.2% (7) 3.7% (3) % (N) ofpatients unless stated. All pts on background of max tolerated statin ±other lipid-lowering therapy. ^(†)Diagnosis of heFH must be made eitherby genotyping or by clinical criteria. For those patients not genotyped,the clinical diagnosis may be based on either the Simon Broome criteriafor definite FH or the WHO/Dutch Lipid Network criteria with a scoreof >8 points.

TABLE 17 Disease Characteristics and Other Relevant Baseline Data -Randomized Population Alirocumab 75 P Value Placebo Q2W/Up150 Q2W Allvs. (N = 82) (N = 167) (N = 249) Placebo Type of hypercholesterolemiaHeterozygous Familial Hypercholesterolemia 82 (100%)  167 (100%)  249(100%)  (heFH) Non-Familial Hypercholesterolemia (non-FH)  0 0  0  Timefrom hypercholesterolemia diagnosis (years) Number 82 167   249   0.4938Mean (SD) 12.7 (8.8)    12.9 (7.9)    12.8 (8.2)    Median   10.8 12.311.5 Min:Max 0:42 0:40 0:42 Confirmation of diagnosis* By genotyping 67(81.7%) 117 (70.1%)  184 (73.9%)  By WHO/Simon Broome 18 (22.0%) 52(31.1%) 70 (28.1%) Definite/Certain 18 (22.0%) 52 (31.1%) 70 (28.1%)*heFH diagnosis can be confirmed by both genotyping and WHO or SimonBroome criteria. Note: p-values comparing baseline data betweentreatment groups are provided for descriptive purpose, as a screeningtool, using Fisher exact test for qualitative data and the asymptoticone-way ANOVA test for Wilcoxon scores (Krukal-Wallis test) forcontinuous data.

TABLE 18 Background LMT at Randomization - Randomized PopulationAlirocumab 75 Placebo Q2W/Up150 Q2W All P = Value (N = 82) (N = 167) (N= 249) vs. Placebo Any statin 82 (100%) 167 (100%) 249 (100%) Takinghigh intensity 72 (87.8%) 144 (86.2%) 216 (86.7%) 0.8434 statinAtorvastatin daily dose (mg) 10 2 (2.4%) 2 (1.2%) 4 (1.6%) 20 0 8 (4.8%)8 (3.2%) 40 13 (15.9%) 27 (16.2%) 40 (16.1%) 80 16 (19.5%) 28 (16.8%) 44(17.7%) Other doses 1 (I.2%) 0 1 (0.4%) Rosuvastatin daily dose (mg)  51 (1.2%) 1 (0.6%) 2 (0.8%) 10 2 (2.4%) 4 (2.4%) 6 (2.4%) 20 8 (9.8%) 30(18.0%) 38 (15.3%) 40 33 (40.2%) 59 (35.3%) 92 (36.9%) Other doses 1(1.2%) 1 (0.6%) 2 (0.8%) Simvastatin daily dose (mg) 10 1 (1.2%) 0 1(0.4%) 20 1 (1.2%) 3 (1.8%) 4 (1.6%) 40 0 3 (1.8%) 3 (1.2%) 80 3 (3.7%)1 (0.6%) 4 (1.6%) Other doses 0 0 0 Any LMT other than 57 (69.5%) 117(70.1%) 174 (69.9%) 1.0000 statins* Any LMT other than 54 (65.9%) 115(68.9%) 169 (67.9%) nutraceuticals Ezetimibe 53 (64.6%) 112 (67.1%) 165(66.3%) Nutraceuticals 7 (8.5%) 8 (4.8%) 15 (6.0%) Note: p = valuescomparing baseline data between treatment groups are provided fordescriptive purpose, as a screening tool, using Fisher exact test. *incombination with statins or not.

TABLE 19 Cardiovascular History and Risk Factors Breakdown AlirocumabPlacebo Characteristic (N = 323) (N = 163) CHD history 34.1% (57) 37.8%(31) Acute MI 16.2% (27) 17.1% (14) Silent MI 0.6% (1) 2.4% (2) Unstableangina 9.0% (15) 9.8% (8) Coronary revasc. 27.5% (46) 29.3% (24) Otherclinically significant CHD 16.2% (27) 20.7% (17) CHD risk equivalents9.0% (15) 4.9% (4) Ischemic stroke 3.0% (5) 1.2% (1) Peripheral arterialdisease 3.0% (5) 1.2% (1) Moderate CKD 1.2% (2) 1.2% (1) Diabetes + 2 ormore risk factors 3.0% (5) 2.4% (2) % (N) of patients unless stated. Allpts on background of max tolerated statin ± other lipid-lowering therapy

TABLE 20 Lipid Efficacy Parameters at Baseline - Quantitative Summary inConventional Units - Randomized Population Alirocumab 75 P Value PlaceboQ2W/Up150 Q2W All vs. (N = 82) (N = 167) (N = 249) Placebo CalculatedLDL-C (mg/dL) Number 82 167 249 0.8507 Mean (SD) 134.0 (41.4) 134.6(41.1) 134.4 (41.1) Median  126.0   128.0   126.0 Q1:Q3 109.0:151.0107.0:154.0 108.0:151.0 Min:Max  74:295  58:303  58:303 Measured LDL-C(mg/dL) Number 70 149 219 0.6375 Mean (SD) 130.2 (36.6) 132.6 (40.6)131.8 (39.3) Median  125.5   126.0   126.0 Q1:Q3 104.0:145.0 104.0:149.0104.0:147.0 Min:Max  71:249  49:310  49:310 HDL-C (mg/dL) Number 82 167249 0.4437 Mean (SD) 54.2 (15.7) 52.6 (15.7) 53.1 (15.7) Median   51.0  50.0   51.0 Q1:Q3 42.0:63.0 42.0:61.0 42.0:62.0 Min:Max  25:103 24:110  24:110 Total-C (mg/dL) Number 82 167 249 0.9589 Mean (SD) 211.7(45.6) 211.6 (45.8) 211.6 (45.6) Median  200.0   205.0   202.0 Q1:Q3179.0:237.0 178.0:242.0 179.0:239.0 Min:Max 133:376 123:391 123:391Non-HDL-C (mg/dL) Number 82 167 249 0.8208 Mean (SD) 157.5 (43.7) 159.0(44.8) 158.5 (44.4) Median  150.5   147.0   149.0 Q1:Q3 129.0:170.0127.0:181.0 127.0:177.0 Min:Max  93:320  76:326  76:326 Fasting TGs(mg/dL) Number 82 167 249 0.6593 Mean (SD) 116.6 (56.8) 123.2 (69.3)121.0 (65.4) Median  100.5   105.0   104.0 Q1:Q3  81.0:136.0  81.0:144.0 81.0:141.0 Min:Max  47:366  46:581  46:581 Apo-B (mg/dL) Number 81 167248 0.9533 Mean (SD) 107.7 (23.9) 107.9 (27.4) 107.9 (26.3) Median 103.0   102.0   102.0 Q1:Q3  91.0:116.0  91.0:122.0  91.0:121.0 Min:Max 74:187  57:208  57:208 Apo-A1 (mg/dL) Number 81 167 248 0.3472 Mean(SD) 148.9 (29.6) 146.3 (29.4) 147.2 (29.4) Median  150.0   142.0  144.5 Q1:Q3 129.0:166.0 127.0:160.0 128.0:162.5 Min:Max  82:223 90:252  82:252 Apo-B/Apo-A1 (ratio) Number 81 167 248 0.7518 Mean (SD)0.8 (0.2) 0.8 (0.2) 0.8 (0.2) Median   0.7    0.7    0.7 Q1:Q3 0.6:0.80.6:0.9 0.6:0.9 Min:Max 0:1 0:2 0:2 Lipoprotein-(a) (mg/dL) Number 81167 248 0.9910 Mean (SD) 50.9 (59.7) 49.8 (69.2) 50.2 (66.1) Median  21.0   22.0   22.0 Q1:Q3  7.0:76.0  8.0:70.0  7.5:75.0 Min:Max  2:232 2:555  2:555 Total-C/HDL-C (ratio) Number 82 167 249 0.6572 Mean (SD)4.2 (1.3) 4.3 (1.5) 4.3 (1.5) Median   3.9    3.9    3.9 Q1:Q3 3.3:4.83.3:5.0 3.3:4.9 Min:Max 2:9  2:11  2:11 Note: p-values comparingbaseline data between treatment groups are provided for descriptivepurpose, as a screening tool, using the asymptotic one-way ANOVA testfor Wilcoxon scores (Kruskal-Wallis test).

The collection of measured LDL-C was not planned in the initial protocoland was added in an amendment. Therefore, measured LDL-C values areavailable for fewer patients compared to calculated LDL-C values.

Extent of Exposure

Exposure to injections was similar across treatment groups with a meanexposure of approximately 58-60 weeks. Alirocumab treated patients wereexposed for 2-75.9 weeks and placebo treated patients for 11.6-75.7weeks. The majority (93.5%:97.5%, alirocumab:placebo, respectively) ofpatients were treated for more than 52 weeks.

In the alirocumab group, among the 158 patients who received at leastone injection after Week 12, 61 (38.6%) patients received automaticup-titration in a blinded manner at Week 12 from alirocumab 75 mg Q2W to150 mg Q2W. 26 patients were not given the opportunity to up-titrate atWeek 12 due to missing Week 8 LDL-C values at the time of theup-titration decision. Of the 26 patients missing the Week 8 LDL-Cvalue, 4 alirocumab patients should have been up-titrated based on thenow available Week 8 LDL-C data. The remaining patients were either inthe placebo treatment group, or the Week 8 LDL-C visits for thealirocumab patients were below the LDL-C<70mg/dL cut-off forup-titration.

Efficacy Analyses Primary Efficacy Analysis in the ITT Population

The primary endpoint (percent change in calculated LDL-C from baselineto Week 24) analysis is provided based on a MMRM model on the ITTpopulation, using LS means estimates at Week 24. This repeated measuresapproach includes all LDL-C values collected on-treatment andoff-treatment up to Week 52. At Week 24, 3 (3.7%) patients in theplacebo group and 9 (5.4%) patients in the alirocumab group did not havea calculated LDL-C value (Table 15). These missing values were accountedfor by the MMRM model.

The primary efficacy analysis showed a statistically significantdecrease in percent change from baseline calculated LDL-C at Week 24 inthe ITT analysis for the alirocumab treatment group (LS mean=−48.7%) ascompared to placebo (LS mean=2.8%). The LS mean difference between thealirocumab treatment group and the placebo treatment groups is −51.4%(p<0.0001). 81.4% of HeFH patients in the alirocumab group achieved theLDL-C goals at 24 weeks, compared to 11.3% for the placebo group.

TABLE 21 Percent Change from Baseline in Calculated LDL-C at Week 24(ITT Analysis): MMRM Analysis - ITT Population Alirocumab 75 CalculatedLDL Placebo Q2W/Up150 Q2W Cholesterol (N = 81) (N = 166) Baseline(mmol/L) Number 81 166 Mean (SD) 3.470 (1.078) 3.486 (1.069) Median   3.263     3.289 Min:Max 1.92:7.64 1.50:7.85 Baseline (mg/dL) Number81 166 Mean (SD) 134.0 (41.6) 134.6 (41.3) Median  126.0   127.0 Min:Max 74:295  58:303 Week 24 percent change from baseline (%) LS Mean (SE)2.8 (2.8) −48.7 (1.9) LS mean difference (SE) vs −51.4 (3.4) Placebo 95%CI (−58.1 to −44.8) p-value vs. Placebo    <.0001 Note: Lean-squares(LS) means, standard errors (SE) and p-value taken from MMRM(mixed-effect model with repeated measures) analysis. The model includesthe fixed categorical effects of treatment group, randomization strataas per IVRS, time point, treatment-by-time point interaction,strata-by-time point interaction, as well as the continuous fixedcovariates of baseline calculated LDL-C value and baseline value bytime-point interaction. MMRM model and baseline description run onpatients with a baseline value and a post-baseline value in at least oneof the analysis windows used in the model. The p-value is followed by a‘*’ if statistically significant according to the fixed hierarchicalapproach used to ensure a strong control of the overall type-1 errorrate at the 0.05 level.

Calculated LDL-C Over Time

FIG. 4 is a graph that shows the LDL-C LS mean (+/−SE) percent changefrom baseline over time for the ITT population. Note: Least-squares (LS)means and standard errors (SE) taken from MMRM (mixed-effect model withrepeated measures) analysis.

The model includes the fixed categorical effects of treatment group,time point, treatment-by-time point interaction, as well as thecontinuous fixed covariates of baseline LDL-C value and baselineLDL-C-by-time point interaction.

TABLE 22 Calculated LDL-C Over Time - ITT Population Alirocumab 75Placebo Q2W/Up150 Q2W (N = 81) (N = 166) Percent Percent Change changeChange change Calculated from from from from LDL-C Value baselinebaseline Value baseline baseline LS mean (SE) (mmol/L) Baseline 3.470(0.120) NA NA 3.486 (0.083) NA NA Week 4 3.485 (0.077) 0.004 (0.077) 1.1(2.0) 1.924 (0.054) −1.56 (0.054) −45.2 (1.4) Week 8 3.561 (0.090) 0.081(0.090) 3.3 (2.4) 1.913 (0.063) −1.57 (0.063) −45.3 (1.7) Week 12 3.585(0.097) 0.104 (0.097) 4.6 (2.6) 1.960 (0.068) −1.52 (0.068) −43.8 (1.8)Week 16 3.508 (0.101) 0.028 (0.101) 2.4 (2.7) 1.649 (0.071) −1.83(0.071) −51.9 (1.9) Week 24 3.537 (0.103) 0.057 (0.103) 2.8 (2.8) 1.754(0.072) −1.73 (0.072) −48.7 (1.9) Week 36 3.603 (0.117) 0.122 (0.117)5.1 (3.2) 1.788 (0.081) −1.69 (0.081) −48.0 (2.2) Week 52 3.718 (0.125)0.237 (0.125) 8.4 (3.3) 1.708 (0.088) −1.77 (0.088) −50.3 (2.3) Week 643.601 (0.107) 1.657 (0.075) Week 78 3.574 (0.109) 1.806 (0.076) LS mean(SE) (mg/dL) Baseline 134.0 (4.6) NA NA 134.6 (3.2) NA NA Week 4 134.6(3.0) 0.2 (3.0) 1.1 (2.0) 74.3 (2.1) −60.1 (2.1) −45.2 (1.4) Week 8137.5 (3.5) 3.1 (3.5) 3.3 (2.4) 73.9 (2.4) −60.5 (2.4) −45.3 (1.7) Week12 138.4 (3.7) 4.0 (3.7) 4.6 (2.6) 75.7 (2.6) −58.7 (2.6) −43.8 (1.8)Week 16 135.5 (3.9) 1.1 (3.9) 2.4 (2.7) 63.7 (2.7) −70.7 (2.7) −51.9(1.9) Week 24 136.6 (4.0) 2.2 (4.0) 2.8 (2.8) 67.7 (2.8) −66.7 (2.8)−48.7 (1.9) Week 36 139.1 (4.5) 4.7 (4.5) 5.1 (3.2) 69.0 (3.1) −65.3(3.1) −48.0 (2.2) Week 52 143.6 (4.8) 9.2 (4.8) 8.4 (3.3) 65.9 (3.4)−68.4 (3.4) −50.3 (2.3) Week 64 139.0 (4.1) 64.0 (2.9) Week 78 138.0(4.2) 69.7 (2.9) * Baseline is described using means and standarderrors. Note: Least-squares (LS) means, standard errors (SE) and p-valuetaken from MMRM (mixed-effect model with repeated measures) analysis.The model includes the fixed categorical effects of treatment group,randomization strata as per IVRS, time point, treatment-by-time pointinteraction, strata-by-time point interaction, as well as the continuousfixed covariates of baseline LDL-C value and baseline LDL-C value bytime point interaction. MMRM model and baseline description run onpatients with a baseline value and a post-baseline value in at least oneof the analysis windows used in the model.

Sensitivity to Serious GCP Non-Compliance

There was no site with serious GCP non-compliance in this study.

Key Secondary Efficacy Analysis

The following table summarizes analysis results on all key secondaryendpoints in the hierarchical order for statistical testing at the 0.05significance level. This study has achieved statistically significanteffects in favor of the alirocumab treated patients for all but the lastone in the hierarchy (i.e., Apo A-1−Percent change from baseline to Week12) of the key secondary efficacy endpoints.

For clarification, the ITT analysis is defined for patients in the ITTpopulation and includes all endpoint assessments in an analysis window,regardless of study treatment dosing status (i.e. includespost-treatment assessments). The on-treatment analysis is defined forpatients in the mITT population and includes all endpoint assessmentsfrom the first double-blind study drug injection up to the day of lastinjection+21 days (i.e. includes assessments in the efficacy treatmentperiod).

TABLE 23 Summary of Key Secondary Efficacy Endpoints AlirocumabEndpoint/Analysis Placebo Result Result Comparison P-value 1. LDL-C atWK 24 - ITT LS mean: 2.8% LS mean: −48.7% Diff: −51.4% <.0001 analysis2. LDL-C at WK 24 - on- LS mean: 2.7% LS mean: −49.4% Diff: −52.2%<.0001 treatment analysis 3. LDL-C at WK 12 - ITT LS mean: 4.6% LS mean:−43.8% Diff: −48.4% <.0001 analysis 4. LDL-C at WK 12 - on- LS mean:4.6% LS mean: −44.2% Diff: −48.8% <.0001 treatment analysis 5. Apo B atWK 24 - ITT LS mean: −3.5% LS mean: −42.8% Diff: −39.3% <.0001 analysis6. Apo B at WK 24 - on- LS mean: −3.5% LS mean: −43.2% Diff: −39.8%<.0001 treatment analysis 7. Non-HDL-C at WK 24 - LS mean: 3.1% LS mean:−42.6% Diff: −45.7% <.0001 ITT analysis 8. Non-HDL-C at WK 24 - LS mean:3.1% LS mean: −43.2% Diff: −46.4% <.0001 on-treatment analysis 9. TotalCholesterol at WK LS mean: 2.1% LS mean: −30.6% Diff: −32.8% <.0001 24 -ITT analysis 10. Apo B at WK 12- ITT LS mean: −0.9% LS mean: −35.4%Diff: −34.5% <.0001 analysis 11. Non-HDL-C at WK 12- LS mean: 4.1% LSmean: −37.9% Diff: −42.0% <.0001 ITT analysis 12. Total Cholesterol atLS mean: 3.4% LS mean: −26.6% Diff: −29.9% <.0001 WK 12 - ITT analysis13. LDL-C at WK 52 - ITT LS mean: 8.4% LS mean: −50.3% Diff: −58.8%<.0001 analysis 14. Very High CV LDL-C <70 Proportion = 1.3% Proportion= 81.4% Odds Ratio = 52.2 <.0001 mg/dL OR High CV LDL-C <100 mg/dL at WK24 - ITT analysis 15. Very High CV LDL-C <70 Proportion = 1.6%Proportion = 82.1% Odds Ratio = 53.3 <.0001 mg/dL OR High CV LDL-C <100mg/dL at WK 24 - on- treatment analysis 16. LDL-C <70 mg/dL atProportion = 1.2% Proportion = 68.2% Odds Ratio = 239.7 <.0001 WK 24 -ITT analysis 17. LDL-C <70 mg/dL at Proportion = 1.3% Proportion = 68.8%Odds Ratio = 240.6 <.0001 WK 24 - on-treatment analysis 18. Lp(a) at WK24 - ITT LS mean: −10.0% LS mean: −30.3% Diff: −20.3% <.0001 analysis19. HDL-C at WK 24 - ITT LS mean: −0.8% LS mean: 6.0% Diff: 6.8% 0.0009analysis 20. Fasting Triglycerides at LS mean: 0.4% LS mean: −10.5%Diff: −10.9% 0.0017 WK 24 - ITT analysis 19. Apo A-1 at WK 24 - ITT LSmean: −1.6% LS mean: 2.8% Diff: 4.4% 0.0062 analysis 20. Lp(a) at WK12 - ITT LS mean: −5.6% LS mean: −24.7% Diff: −19.1% <.0001 analysis 21.HDL-C at WK 12 - ITT LS mean: 1.7% LS mean: 6.0% Diff: 4.3% 0.0147analysis 22. Fasting Triglycerides at LS mean: 0.9% LS mean: −8.0% Diff:−8.9% 0.0258 WK 12 - ITT analysis Apo A-1 at WK 12 - ITT LS mean: −1.9%LS mean: 0.4% Diff: 2.3% 0.1475 analysis Hierarchical testing terminated

All the key secondary efficacy endpoints, except for percent change inApo A-1 from baseline to Week 12 in ITT population, achievedstatistically significant effects in favor of the alirocumab treatedpatients according to the hierarchical testing procedure.

The key secondary efficacy analysis for percent change from baseline ofcalculated LDL-C to week 24 in the mITT population (on-treatmentanalysis) showed consistent results with the ITT analysis with astatistically significant decrease in calculated LDL-C in the alirocumabtreatment group (LS mean=−49.4%) as compared to placebo (LS mean=2.7%).The LS mean treatment difference between the alirocumab-treated patientsand the placebo-treated patients is −52.2% (p<0.0001). Indeed, fewpatients had LDL-C values collected post-treatment (i.e., more than 21days after last injection) at Week 24: 1 patient (1.2%) in the placebogroup and 2 patients (1.2%) in the alirocumab group.

The decrease in percent change in Apo A-1 from baseline to Week 24 inthe ITT analysis was non-statistically significant: LS mean versusbaseline was 0.4% in the alirocumab group and −1.9% in the placebo group(LS mean difference vs. placebo of 2.3%, p=0.1475).

Calculated Ldl-C Over Time (Includes Observed Data)

FIG. 5 is a graph that shows the LDL-C LS mean (+/−SE) percent changefrom baseline during the efficacy treatment period over time for themITT Population.

Summary

Overall, demographic characteristics, baseline disease characteristics,baseline efficacy lipid parameters, LMT history and background LMT usewere comparable between patients randomized to the alirocumab group andpatients randomized to the placebo group. Particularly, the mean (SD)baseline LDL-C in the alirocumab group was 134.6 (41.1) mg/dL comparedto that in the placebo group being 134.0 (41.4) mg/dL.

The primary efficacy endpoint and all the key secondary endpoints,except for percent change in Apo A-1 from baseline to Week 12 in ITTpopulation (ITT analysis), achieved statistically significant benefit infavor of Alirocumab-treated patients according to the hieracrchicaltesting procedure.

Summary Safety Results

A total of 248 patients were randomized and received at least a partialdose of study treatment (Safety Population). Below is a high-levelsummary of adverse events and events of interest.

TABLE 24 Overview of Adverse Event Profile: Treatment Emergent AdverseEvents - Safety Population Alirocumab 75 Placebo Q2W/Up150 Q2W (N = 81)(N = 167) Patients with any TEAE 62 (76.5%) 117 (70.1%) Patients withany treatment 7 (8.6%) 10 (6.0%) emergent SAE Patients with any TEAEleading 0 0 to death Patients with any TEAE leading 1 (1.2%)  5 (3.0%)to permanent treatment discontinuation TEAE: Treatment emergent adverseevent, SAE: Serious adverse event n(%) = number and percentage ofpatients with at least one TEAE

Treatment-emergent SAEs occurred in a total of 17 patients, specifically10 (6.0%) patients in the alirocumab treatment group and 7 (8.6%)patients in the placebo treatment group. There were no more than 2reports in any SOC for either treatment group and no individual SAE wasreported more than once in either treatment group.

No patient deaths were reported at the time of this first-step analysis.

A total of 6 patients prematurely discontinued study treatment due to aTEAE. Specifically, 5 (3.0%) patients in the alirocumab treatment groupdiscontinued treatment early for rectal adenocarcinoma, diarrhoea,nausea, angioedema, asthenia, and alanine aminotransferase increased.One (1.2%) patient in the placebo treatment group discontinued due tosyncope.

TEAEs occurred in 117 (70.1%) patients in the alirocumab treatment groupand 62 (76.5%) patients in the placebo treatment group. The TEAEs thatoccurred in ≥5% of patients in any treatment group are: injection sitereaction (10.8% vs. 7.4% in alirocumab and placebo group, respectively),headache (8.4% vs. 8.6% in alirocumab and placebo group, respectively),myalgia (6.0% vs. 6.2% in alirocumab and placebo group, respectively),and diarrhoea (5.4% vs. 1.2% in alirocumab and placebo group,respectively).

For TEAEs of special interest (AESIs), results are presented bypre-defined SMQ preferred term groupings.

Treatment-emergent injection site reactions (ISRs) occurred in 18(10.8%) patients in the alirocumab treatment group and 6 (7.4%) patientsin the placebo treatment group. None of the AEs were serious.

General Allergic TEAEs, identified through the MedDRA SMQ of“Hypersensitivity” occurred in 17 (10.2%) patients in the alirocumabtreatment group and 6 (7.4%) patients in the placebo treatment group.None of the AEs were serious.

Treatment-emergent neurologic disorders occurred in 7 (4.2%) patients inthe alirocumab treatment group and 2 (2.5%) patients in the placebotreatment group. In the alirocumab group, the PTs were: hypoaesthesia in4 (2.4%) patients, paraesthesia in 2 (1.2%), and balance disorder in 1(0.6%). None of the AEs were serious.

Treatment-emergent neurocognitive disorders occurred in 0 (0.0%)patients in the alirocumab treatment group and 1 (1.2%) patients in theplacebo treatment group. The AE was not serious.

A total of 9 (5.4%) patients in the alirocumab treatment group and 0(0.0%) patients in the placebo treatment group had 2 consecutivecalculated LDL-C measurements below 25 mg/dL. For those patients with 2consecutive calculated LDL-C measurements below 25 mg/dL, TEAEs occurredin 3 (33.3%) patients in the alirocumab treatment. The PTs were:influenza, influenza like illness, and nasopharyngitis. None of theseAEs were serious, nor were they AESIs.

Conclusion

The following conclusions can be drawn from this early review of thestudy data: 1) the study achieved the primary efficacy endpoint with astatistically significant reduction in calculated LDL-C in thealirocumab treated patients; 2) this study also achieved all of the keysecondary efficacy endpoints, except for the last endpoint (Apo A-1 atWeek 12 in the ITT population (ITT analysis)); and 3) based on theavailable data at the time of this first step analysis, subcutaneousadministration of alirocumab to patients with heterozygous familialhypercholesterolemia and an LDL-C>70 mg/dL or LDL-C>100 mg/dL, dependingon history of MI or stroke at baseline, was generally safe and welltolerated.

Summary of Pooled Data from FH I and FH ll Studies

From the pooled data of the FHI and FHII studies the followingconclusions can be drawn: 1) self-administered alirocumab producedsignificantly greater LDL-C reductions vs. placebo after 24 weeks (LSmean difference of 51.4-57.9%); 2) the majority of patients (>70%)achieved their LDL-C goals at Week 24; 3) LDL-C reductions of 47.1-50.3%at Week 52 were achieved with alirocumab; 4) mean LDL-C levels of1.7-1.9 mmol/L (65.9-74.3 mg/dL) at Week 52 were achieved withalirocumab; 5) approximately 50% of patients did not require uptitrationto alirocumab 150 mg Q2W suggesting that 75 mg Q2W may be sufficient formany patients; and 6) TEAEs occurred in a similar frequency in thealirocumab and placebo arms.

Specifically, the combined data of the FHI and FHII studies shows thatalirocumab produced a significant reduction in LDL-C at week 24 relativeto placebo. The LS mean (SE) % change from baseline at week 24 was−48.8% for the alirocumab group (N=488), compared to 7.1% for theplacebo group (N=244). The LS mean difference (SE) vs. placebo was−55.8% (2.1) (P<0.0001). Moreover, only 42% of of alirocumab patientsrequired uptitration at Week 12 to the 150 mg Q2W dose.

The LS mean (SE) calculated LDL-C values versus time for the ODYSSEY FHI and FH II studies are shown in FIG. 8. The values indicted on thegraph are the LS mean % change from baseline to week 24 and week 52.FIG. 9 is a graph showing the LS mean (SE) calculated LDL-C valuesversus time for the ODYSSEY FH I and FH II studies. The values indictedbelow the graph are the numbers of patients analyzed at the varioustimepoints.

Among patients who received double-blind treatment for at least 12weeks, 176/311 (56.6%) in FH I and 97/158 (61.4%) in FH II had LDL-Clevels<1.8 mmol/L at week 8 and were maintained on alirocumab 75 mg Q2W.LDL-C levels were stable over time in these patients (FIG. 10). Forpatients in FH I who received dose increase to 150 mg Q2W, mean LDL-Clevels were 2.7 mmol/L (104.3 mg/dL) at week 12 and 2.0 mmol/L (78.5mg/dL) at week 24. Corresponding values in FH II were 2.6 mmol/L (98.6mg/dL) at week 12 and 1.9 mmol/L (71.8 mg/dL) at week 24.

Subgroup analyses of the primary efficacy endpoint showed consistentreduction of calculated LDL-C across a range of demographic and baselinecharacteristics (FIGS. 11A-11C). The percentage reduction in LDL-C(alirocumab vs placebo) was 60.1% in males and 50.6% in females (pooleddata from FH I and FH II), with a P-value for interaction of 0.0267. Inthe individual studies, LDL-C reductions (vs placebo) were 62.6% formales and 51.9% for females in FH I, and 53.5% for males and 49.2% forfemales in FH II.

A summary of interim safety data pooled from the FH I and FH II studiesis set forth in Table 25A. All data was collected up to last patientvisit at week 52. The percentage of patients who experienced TEAEs,serious AEs, and TEAEs leading to treatment discontinuation werecomparable between treatment groups in the individual studies (Table25B). A higher proportion of patients experienced injection sitereactions in the alirocumab groups vs placebo in FH I (12.4% vs 11.0%)and FH II (11.4% vs 7.4%). Most of the injection site reactions wereclassified as mild in intensity. No injection site reaction led to studydrug discontinuation. None of the reported neurological or allergicevents (Table 3) were serious. Pruritus was reported in two (0.6%) andthree (1.8%) alirocumab-treated patients in FH I and II, respectively,and one placebo-treated patient in each study (0.6% and 1.2%,respectively). Few neurocognitive events were reported with alirocumab(2 [0.6%] in FH I, none in FH II) or placebo (2 [1.2%] in FH I, 1 [1.2%]in FH II; Table 3). In FH I and FH II, respectively, 85.8% and 91.6% ofalirocumab-treated patients (87.7% and 90.1% of placebo) received studytreatment for 76 weeks.

TABLE 25A Interim Safety Analysis (Pooled Data from FH I and FH IIStudies) % (N) of patients All pts on background of max tolerated statin± other Alirocumab Placebo lipid-lowering therapy (N = 489) (N = 244)TEAEs 74.8% (366) 75.4% (184) Treatment-emergent SAEs 10.0% (49) 9.0%(22) TEAEs leading to death 0.8% (4) 0 TEAEs leading to 3.1% (15) 3.7%(9) discontinuation Adverse Events of Interest Adjudicated CV events1.6% (8) 1.2% (3) Injection-site reactions 11.5% (56) 9.0% (22)Neurocognitive disorders 0.2% (1) 1.2% (3) ALT >3 × ULN 2.1% (10/488)1.2% (3/244) Creatine kinase >3 × ULN 3.5% (17/483) 6.2% (15/243) OtherAdverse Events Nasopharyngitis 10.2% (50) 11.1% (27) Influenza 8.8% (43)6.1% (15) Headache 5.5% (27) 6.6% (16) Back pain 4.9% 3.7% Upperrespiratory tract 4.3% 4.9% infection arthralgia 3.9% 4.9% urinary tractinfection 3.9% 2.5% Diarrhoea 3.7% 2.5% Myalgia 3.5% 4.9%gastroenteritis 3.3% 3.3% sinusitis 3.3% 2.9% muscle spasms 3.1% 0.4%dizziness 2.9% 3.7% nausea 2.5% 3.7% pain in extremities 1.8% 3.3%fatigue 3.1% 2.5% influenza like illness 2.9% 2.0% bronchitis 2.7% 2.5%abdominal pain 2.5% 1.6% blood creatinine 2.5% 2.9% phosphokinase cough1.6% 2.5% hypertension 1.6% 2.5% cystitis 1.2% 1.6% neck pain 0.4% 2.0%

TABLE 25B Final Safety Analysis (Pooled Data from FHI and FHII Studies)FH I FH II Alirocumab Placebo Alirocumab Placebo n (%) (n = 322) (n =163) (n = 167) (n = 81) TEAEs 263 (81.7) 129 (79.1) 125 (74.9) 66 (81.5)Treatment-emergent SAEs 44 (13.7) 22 (13.5) 15 (9.0) 8 (9.9) TEAEsleading to death^(a) 6 (1.9) 0 0 0 TEAEs leading to treatment 11 (3.4)10 (6.1) 6 (3.6) 1 (1.2) discontinuation TEAEs occurring in ≥5% patients(in any group) Injection site reaction 40 (12.4) 18 (11.0) 19 (11.4) 6(7.4) Exact Fisher test p-value^(b) 0.77 0.38 Nasopharyngitis 36 (11.2)12 (7.4) 21 (12.6) 18 (22.2) Upper respiratory tract infection 22 (6.8)14 (8.6) 5 (3.0) 1 (1.2) Arthralgia 20 (6.2) 9 (5.5) 8 (4.8) 7 (8.6)Influenza 20 (6.2) 10 (6.1) 24 (14.4) 7 (8.6) Back pain 18 (5.6) 7 (4.3)12 (7.2) 6 (7.4) Sinusitis 17 (5.3) 7 (4.3) 1 (0.6) 2 (2.5) Headache 15(4.7) 9 (5.5) 16 (9.6) 7 (8.6) Diarrhoea 10 (3.1) 5 (3.1) 11 (6.6) 1(1.2) Bronchitis 10 (3.1) 9 (5.5) 4 (2.4) 1 (1.2) Dizziness 7 (2.2) 6(3.7) 8 (4.8) 5 (6.2) Myalgia 6 (1.9) 11 (6.7) 10 (6.0) 5 (6.2)Influenza like illness 6 (1.9) 1 (0.6) 9 (5.4) 5 (6.2) Safety events ofinterest Positively adjudicated CV events 8 (2.5) 3 (1.8) 2 (1.2) 1(1.2) General allergic TEAEs^(c) 28 (8.7) 16 (9.8) 19 (11.4) 5 (6.2)Neurological TEAEs^(c) 12 (3.7) 7 (4.3) 7 (4.2) 2 (2.5) Neurocognitivedisorders^(c) 2 (0.6) 2 (1.2) 0 1 (1.2) Development/worsening of 6 (1-9)4 (2.5) 4 (2.4) 2 (2.5) diabetes^(b) Ophthalmologic disorders^(c) 3(0.9) 4 (2.5) 3 (1.8) 1 (1.2) Alanine aminotransferase >3 × 5/322 (1.6)2/163 (1.2) 6/166 (3.6) 1/81 (1.2) ULN Creatine kinase >3 × 13/318 (4.1)10/163 (6.1) 8/165 (4.8) 6/80 (7.5) ULN

Example 4 A Randomized, Double-Blind, Placebo-Controlled, Parallel GroupStudy to Evaluate the Efficacy and Safety of Alirocumab in Patients WithHeterozygous Familial Hypercholesterolemia and LDL-C higher or equal to160 mg/dL with Their Lipid-Modifying Therapy Introduction

This study included patients with heterozygous familialhypercholesterolemia (heFH) with or without a history of documented MIor ischemic stroke.

The objective of the present study was to assess the efficacy and safetyof Alirocumab in patients with heFH whose LDL-C level was higher than orequal to 160 mg/dL (4.14 mmol/L) on maximally tolerated statin therapywith or without additional LMT.

This specific study (FIG. 6) was undertaken to demonstrate in heFHpatients, with LDL-C higher or equal to 160 mg/dL, that Alirocumab 150mg Q2W as add-on therapy to statin+/−other LMT causes a statisticallysignificant and clinically meaningful reduction in LDL-C. Thispopulation with such a high LDL-C level despite an optimized LMTrepresents a highest risk group with a well-identified unmet medicalneed that may be addressed by adding Alirocumab to their LDL-C loweringtherapies.

Study Objectives

The primary objective of the study was to demonstrate the reduction ofLDL-C by Alirocumab as add-on therapy to stable maximally tolerateddaily statin therapy with or without other LMT in comparison withplacebo after 24 weeks of treatment in patients with heterozygousfamilial hypercholesterolemia (heFH) and LDL-C higher than or equal to160mg/dL (4.14 mmol/L).

The secondary objectives were: 1) to evaluate the effect of Alirocumabin comparison with placebo on LDL-C after 12 weeks of treatment; 2) toevaluate the effect of Alirocumab on other lipid parameters (i.e., ApoB, non-HDL-C, total-C, Lp (a), HDL-C, TG, and Apo A-1 levels); 3) toevaluate the long-term effect of Alirocumab on LDL-C; 4) to evaluate thesafety and tolerability of Alirocumab; 5) to evaluate the development ofanti-Alirocumab antibodies.

Study Design

This was a randomized, double-blind, placebo-controlled, parallel-group,unbalanced (2:1, Alirocumab: placebo), multi-center, multi-nationalstudy to assess the efficacy and the safety of Alirocumab in patientswith heterozygous familial hypercholesterolemia (heFH) and LDL-C higheror equal to 160 mg/dL with or without their LMT (i.e., stable maximallytolerated daily statin therapy+/−other LMT). Randomization wasstratified according to prior history of myocardial infarction (MI) orischemic stroke [Yes/No], and statin treatment (atorvastatin 40 to 80 mgdaily or rosuvastatin 20 to 40 mg daily vs. simvastatin whatever thedaily dose, atorvastatin below 40 mg daily or rosuvastatin below 20 mgdaily). After randomization, patients received double-blind studytreatment (either Alirocumab or placebo) every 2 weeks over a period of78 weeks on top of stable maximally tolerated daily statintherapy+/−other LMT.

After completion of the 18-month double-blind treatment period, allpatients who successfully completed the ODYSSEY High FH study had theopportunity to participate in an open-label extension study.Consequently all patients will receive Alirocumab at entry in theopen-label extension study regardless the study treatment they receivedduring the 18-month double-blind treatment period.

The study consisted of 3 periods: screening, double-blind treatment, andfollow up.

The screening period was up to 3 weeks in duration including anintermediate visit during which the patient (or another designatedperson such as spouse, relative, etc.) was trained to self-inject/injectwith placebo for Alirocumab. Eligibility assessments were performed topermit the randomization of the patients into the study.

The double-blind treatment period was a randomized, double-blind studytreatment period of 18 months. The first injection during thedouble-blind period was done at the site on the day of randomization(Week 0 [D1]-V3) and as soon as possible after the call to IVRS/IWRS forrandomization into the study. The subsequent injections were done by thepatient (self-injection) or another designated person (such as spouse,relative, etc.) at a patient-preferred location (home . . . ). Patientsrandomized to Alirocumab received a dose of 150 mg of the IMP fromrandomization (V3) up to Week 76 (i.e., Weeks 0, 2, 4, 6, 8 . . . to76).

The follow-up period (if applicable) was a period of 8 weeks after theend of the DBTP for patients not consenting to participate in theopen-label extension study or if prematurely discontinuing studytreatment.

The laboratory measurement of lipid parameters were performed by acentral laboratory (central lab) during the study.

Patients who achieved 2 consecutive calculated LDL-C levels<25 mg/dL(0.65 mmol/L) during the study were monitored and managed.

Statin and other LMT (if applicable) should have been stable (includingdose) during the first 24 weeks of the DBTP barring exceptionalcircumstances whereby overriding concerns (including but not limited toTG alert posted by the central lab) warrant such changes, as per theInvestigator's judgment. From Week 24 onwards, background LMT wasmodified only under certain conditions as described below.

Patients should have been on a stable diet (NCEP-ATPIII TLC diet orequivalent) throughout the entire study duration from screening, asdescribed above in Example 2 (see Table 1). The dietician or site staffwith appropriate training reviewed the patient's diet at the screeningvisit and periodically throughout the study.

The study duration included a screening period of up to 3 weeks, a78-week DBTP for efficacy and safety assessment, and an 8-weekpost-treatment follow-up period after the last visit of the DBTP forpatients not consenting to participate in the open-label extension studyor if prematurely discontinuing study treatment. Thus, the maximum studyduration per patient was about 89 weeks (i.e., 20 months) (up to 3 weeksscreening+78 weeks double-blind treatment+8 weeks follow-up). The end ofthe study per patient was the last protocol planned visit or theresolution/stabilization of all SAEs, and AESI, whichever came last.

Selection of Patients

The inclusion criteria were: 1) patients with heterozygous familialhypercholesterolemia (heFH)* who were not adequately controlled with amaximally tolerated daily dose of statin,** with or without otherlipid-modifying therapy (LMT) at stable dose prior to the screeningvisit (Week-3).

*Diagnosis of heFH must have been made either by genotyping or byclinical criteria. For those patients not genotyped, the clinicaldiagnosis may have been based on either the Simon Broome criteria with acriteria for definite FH or the WHO/Dutch Lipid Network criteria with ascore>8 points. See criteria described above in Example 2.

Definition of maximally tolerated dose: any of the following wereacceptable): 1) rosuvastatin 20 mg or 40 mg daily; 2) atorvastatin 40 mgor 80 mg daily; 3) simvastatin 80 mg daily (if already on this dosefor >1 year—see exclusion criterion E 06); or 4) patients not able to beon any of the above statin doses, should have been treated with the doseof daily atorvastatin, rosuvastain or simvastatin that was consideredappropriate for the patient as per the investigator's judgment orconcerns. Some examples of acceptable reasons for a patient taking alower statin dose included, but were not limited to: adverse effects onhigher doses, advanced age, low body mass index, regional practices,local prescribing information, concomitant meds, co-morbid conditionssuch as impaired glucose tolerance/impaired fasting glucose.

Patients who met all the above inclusion criteria were screened for thefollowing exclusion criteria, which are sorted and numbered in thefollowing 3 subsections: exclusion criteria related to studymethodology, exclusion criteria related to the background therapies, andexclusion criteria related to Alirocumab.

Exclusion criteria related to study methodology were: 1) patient withoutdiagnosis of heFH made either by genotyping or by clinical criteria; 2)LDL-C<160 mg/dL (<4.14 mmol/L) at the screening visit (Week-3); 3) noton a stable dose of LMT (including statin) for at least 4 weeks and/orfenofibrate for at least 6 weeks as applicable, prior to the screeningvisit (Week-3) or from screening to randomization; 4) currently taking astatin other than simvastatin, atorvastatin, or rosuvastatin; 5)simvastatin, atorvastatin, or rosuvastatin is not taken daily or nottaken at a registered dose; 6) daily doses above atorvastatin 80 mg,rosuvastatin 40 mg or simvastatin 40 mg, (except for patients onsimvastatin 80 mg for more than one year, who are eligible); 7) use offibrates, other than fenofibrate within 6 weeks of the screening visit(Week-3) or between screening and randomization visits; 8) use ofnutraceutical products or over-the-counter therapies that may affectlipids which have not been at a stable dose/amount for at least 4 weeksprior to the screening visit (Week-3) or between screening andrandomization visits; 9) use of red yeast rice products within 4 weeksof the screening visit (Week-3) or between screening and randomizationvisits; 10) patient who has received plasmapheresis treatment within 2months prior to the screening visit (Week-3), or has plans to receive itduring the study; 11) recent (within 3 months prior to the screeningvisit [Week-3] or between screening and randomization visits) MI,unstable angina leading to hospitalization, percutaneous coronaryintervention (PCI), coronary artery bypass graft surgery (CABG),uncontrolled cardiac arrhythmia, stroke, transient ischemic attack(TIA), carotid revascularization, endovascular procedure or surgicalintervention for peripheral vascular disease; 12) planned to undergoscheduled PCI, CABG, carotid, or peripheral revascularization during thestudy; 13) systolic blood pressure>160 mmHg or diastolic bloodpressure>100 mmHg at screening visit or randomization visit; 14) historyof New York Heart Association (NYHA) Class III or IV heart failurewithin the past 12 months; 15) known history of a hemorrhagic stroke;16) age<18 years or legal age of majority at the screening visit(Week-3), whichever is greater; 17) patients not previously instructedon a cholesterol-lowering diet prior to the screening visit (Week-3);18) newly diagnosed (within 3 calendar months prior to randomizationvisit [Week 0]) or poorly controlled (HbA1c>9% at the screening visit[Week-3]) diabetes; 19) presence of any clinically significantuncontrolled endocrine disease known to influence serum lipids orlipoproteins. Note: patients on thyroid replacement therapy can beincluded if the dosage has been stable for at least 12 weeks prior toscreening and between screening and randomization visits, and TSH levelis within the normal range of the Central Laboratory at the screeningvisit; 20) history of bariatric surgery within 12 months prior to thescreening visit (Week-3); 21) unstable weight defined by a variation>5kg within 2 months prior to the screening visit (Week-3); 22) knownhistory of homozygous FH; 23) known history of loss of function of PCSK9(i.e., genetic mutation or sequence variation); 24) use of systemiccorticosteroids, unless used as replacement therapy forpituitary/adrenal disease with a stable regimen for at least 6 weeksprior to randomization visit (Week 0). Note: topical, intra-articular,nasal, inhaled and ophthalmic steroid therapies are not considered as“systemic” and are allowed; 25) use of continuous estrogen ortestosterone hormone replacement therapy unless the regimen has beenstable in the past 6 weeks prior to the Screening visit (Week-2) and noplans to change the regimen during the study; 26) history of cancerwithin the past 5 years, except for adequately treated basal cell skincancer, squamous cell skin cancer or in situ cervical cancer; 27) knownhistory of positive HIV test; 28) patient who has taken anyinvestigational drugs other than the Alirocumab training placebo kitswithin 1 month or 5 half lives, whichever is longer; 29) patient who hasbeen previously treated with at least one dose of Alirocumab or anyother anti-PCSK9 monoclonal antibody in other clinical trials; 30)patient who withdraws consent during the screening period (patient whois not willing to continue or fails to return); 31)conditions/situations such as any clinically significant abnormalityidentified at the time of screening that, in the judgment of theInvestigator or any sub-Investigator, would preclude safe completion ofthe study or constrain endpoints assessment; eg, major systemicdiseases, patients with short life expectancy considered by theInvestigator or any sub-Investigator as inappropriate for this study forany reason, e.g.,: a) deemed unable to meet specific protocolrequirements, such as scheduled visits; b) deemed unable to administeror tolerate long-term injections as per the patient or the Investigator;c) investigator or any sub-Investigator, pharmacist, study coordinator,other study staff or relative thereof directly involved in the conductof the protocol, etc.; d) presence of any other conditions (e.g.,geographic or social . . . ) actual or anticipated, that theInvestigator feels would restrict or limit the patient's participationfor the duration of the study; 32) laboratory findings during screeningperiod (not including randomization Week 0 labs): a) positive test forHepatitis B surface antigen or Hepatitis C antibody; b) positive serumbeta-hCG or urine pregnancy (including Week 0) in women of childbearingpotential; c) triglycerides>400 mg/dL (>4.52 mmol/L) (1 repeat lab isallowed); d) eGFR<30 mL/min/1.73 m2 according to 4-variable MDRD Studyequation (calculated by central lab); e) ALT or AST>3×ULN (1 repeat labis allowed); f) CPK>3×ULN (1 repeat lab is allowed); g) TSH<lower limitof normal (LLN) or >upper limit of normal (ULN) (1 repeat lab isallowed).

Exclusion criteria related to the background therapies were: 1) allcontraindications to the background therapies or warnings/precautions ofuse (when appropriate) as displayed in the respective National ProductLabeling.

Exclusion criteria related to Alirocumab were: 1) known hypersensitivityto monoclonal antibody or any component of the drug product; 2) pregnantor breast-feeding women; and 3) women of childbearing potential notprotected by highly-effective method(s) of birth control (as defined inthe informed consent form and/or in a local protocol addendum) and/orwho are unwilling or unable to be tested for pregnancy. Note: Women ofchildbearing potential must have had a confirmed negative pregnancy testat screening and randomization visits. They must have used an effectivecontraceptive method throughout the entire duration of the studytreatment, and for 10 weeks after the last intake of IMP, and agreed torepeat urine pregnancy test at designated visits. The applied methods ofcontraception had to meet the criteria for a highly effective method ofbirth control according to the “Note for guidance on non-clinical safetystudies for the conduct of human clinical trials and marketingauthorization for pharmaceuticals (CPMP/ICH/286/95)”. Postmenopausalwomen must have been amenorrheic for at least 12 months.

Study Treatments

Sterile Alirocumab drug product was supplied at a concentration of 150mg/mL in histidine, pH 6.0, polysorbate 20, and sucrose. Drug productwas supplied as 1 mL volume in an auto-injector.

Sterile placebo for Alirocumab was prepared in the same formulation asAlirocumab without the addition of protein as 1 mL volume in anauto-injector.

During the double-blind treatment period, Alirocumab or placebo wasadministered subcutaneously every 2 weeks, starting at Week 0 continuingup to the last injection (Week 76) 2 weeks before the end of the doubleblind treatment period. If the injection was scheduled to take place onthe same date as the site visit, then the IMP should have beenadministered after the blood sampling had been completed.

IMP should ideally have been administered every 2 weeks subcutaneouslyat approximately the same time of the day; however it was acceptable tohave a window period of ±3 days. The time of the day was based onpatient's preference.

The following classes of drugs were identified as non-investigationalmedicinal products (NIMP) because the medication was either a backgroundtherapy or a potential rescue medication: statins (rosuvastatin,atorvastatin, simvastatin); cholesterol absorption inhibitors(ezetimibe); bile acid-binding sequestrants (such as cholestyramine,colestipol, colesevelam); nicotinic acid; fenofibrate; omega-3 fattyacids (≥1000 mg daily).

Patients who achieved 2 consecutive calculated LDL-C<25 mg/dL (0.65mmol/L) were monitored.

Patients who had titers at or above 240 for anti-Alirocumab antibodiesat follow-up visit had additional antibody sample(s) at 6 to 12 monthsafter the last dose, and thereafter about every 3 to 6 months untiltiter returned below 240.

Patients were randomized to receive either placebo or Alirocumab duringthe double-blind study treatment period using a ratio 1:2, withpermuted-block randomization. Randomization was stratified according toprior history of myocardial infarction (MI) or ischemic stroke [Yes/No],and statin treatment (atorvastatin 40 to 80 mg daily or rosuvastatin 20to 40 mg daily vs. simvastatin whatever the daily dose, atorvastatinbelow 40 mg daily or rosuvastatin below 20 mg daily).

A concomitant medication was any treatment received by the patientconcomitantly to the study (until follow-up visit). Concomitantmedications were to be kept to a minimum during the study. However, ifthese were considered necessary for the patient's welfare and wereunlikely to interfere with the IMP, they couuld be given at thediscretion of the Investigator, with a stable dose (when possible).Besides the specific information related to concomitant medicationsprovided in this section, any other concomitant medication(s) will beallowed. If the patient had an LDL-C>or equal 160 mg/dL (4.14 mmol/L) atthe screening visit (Week-3) and was treated with a statin only, i.e.without additional LMT, the investigator was to report the reason forthe patient not being on a second LMT. For background LMT, includingstatins, sites must have followed the national product label for thesafety monitoring and management of patients.

Nutraceutical products or over-the-counter therapies that may affectlipids were allowed only if they had been used at a stable dose for atleast 4 weeks prior to screening visit, during the screening period andmaintained during the first 24 weeks of the double-blind treatmentperiod. After the Week 24 visit, modification to these nutraceuticalproducts or over-the-counter therapies was allowed but in general shouldhave been avoided. Examples of such nutraceutical products orover-the-counter therapies included omega-3 fatty acids at doses <1000mg, plant stanols such as found in Benecol, flax seed oil, and psyllium.

Patients must have been on stable maximally tolerated daily registereddoses of statins with other LMT for at least 4 weeks (6 weeks forfenofibrate) before screening visit. During the study, the patientsshould have stayed on these stable maximally tolerated registered dailydoses of statins with other LMT. Lipid profile values from samplesobtained after randomization were blinded. Nevertheless, sites were madeaware of triglyceride alert, as well as rescue threshold of LDL-C valuein order to make decisions on the patient's background LMT. From thescreening visit (Week-3) until Week 24 of the double-blind treatmentperiod, the background LMT should not have been changed. No doseadjustment, discontinuation or initiation of other statins or other LMTshould have taken place during this time, barring exceptionalcircumstances whereby overriding concerns (including but not limited totriglyceride alert posted by the central lab) warranted such changes, asper the investigator's judgment.

For a triglyceride alert (TG≥500 mg/dL (5.65 mmol/L)) that was confirmedby repeat testing, the investigator was to perform investigations,manage the patient, and modify the background LMT as per his/her medicaljudgment.

For a rescue notification of LDL-C at the Week 24 visit and later, i.e.,LDL-C increase>25% as compared to randomization visit LDL-C on twoconsecutive occasions, the investigator should have ensured that noreasonable explanation existed for insufficient LDL-C control (such asan alternative medical cause like corticosteroid use, etc.) and inparticular that: compliance with diet was appropriate, compliance withbackground LMT was appropriate, and study treatment was given asplanned. If any of the above could have reasonably explained theinsufficient LDL-C control, the investigator should have undertakenappropriate action, i.e. stressed the absolute need to be compliant withtreatment, if needed organized a specific interview with a qualifiednutrition professional and stressed the absolute need to be compliantwith diet, and performed a blinded LDL-C assessment within 1 to 2months. If none of the above mentioned reasons could be found, or ifappropriate action failed to decrease LDL-C under the alert value,rescue medication may have been introduced. The effectiveness of anysuch changes were made based on the absence of rescue notification ofLDL-C sent on the blinded lipid testing at the next scheduled lab draw.

If no reason for LDL-C above the threshold value could be found, or ifappropriate action failed to decrease LDL-C below the threshold value,rescue medication may have been introduced. The effectiveness of anysuch changes would be made based on lack of rescue threshold fromblinded lipid testing at the next routinely scheduled lab draw. Patientsper protocol already received a maximum tolerated dose of statin, sostatin up-titration or switch was not an option. For further LDL-Clowering, the investigator may have considered: a cholesterol absorptioninhibitor (ezetimibe), or a bile acid-binding sequestrant (the resinscholestyramine and colestipol, or colesevelam, a nonabsorbable polymer).The following lipid modifying agents may have also been considered:fibrate (Note: Caution should be exercised when combining fibrates withother cholesterol-lowering medications such as statins because of therisk of myopathy. When a fibrate is combined with a statin, fenofibrateis the fibrate of choice because it does not affect statinglucuronidation.); the only fibrate allowed per protocol wasfenofibrate; nicotinic acid (niacin) (Note: Niacin raises blood glucosebut has been shown to be effective in modifying lipid disorders inpeople with diabetes if glucose control is maintained).

In summary, background LMT should not have been modified from screeningto the follow up visit. However, up to Week 24, if a confirmed TG alertwas reached or if there was an overwhelming clinical concern (at thediscretion of the Investigator) then modification of the background LMTwas allowed. From Week 24 onwards, if a confirmed TG alert was reached,or if a rescue threshold for LDL-C was attained (and no other reasonableexplanation exists), or if there was an overwhelming clinical concern(at the discretion of the Investigator) then modification of thebackground LMT was allowed.

Women of childbearing potential were required to take an effectivecontraceptive method throughout the study treatment and for 10 weeksafter the last IMP injection (i.e., Follow-up visit).

Forbidden concomitant medications from the initial screening visit untilthe follow-up visit included the following: statins other thansimvastatin, atorvastatin and rosuvastatin; fibrates, other thanfenofibrate; and red yeast rice products.

Study Endpoints

The primary efficacy endpoint was the percent change in calculated LDL-Cfrom baseline to Week 24, which was defined as: 100×(calculated LDL-Cvalue at Week 24-calculated LDL-C value at baseline)/calculated LDL-Cvalue at baseline. The baseline calculated LDL-C value was the lastLDL-C level obtained before the first double-blind IMP injection. Thecalculated LDL-C at Week 24 was the LDL-C level obtained within the Week24 analysis window and during the main efficacy period. The mainefficacy period was defined as the time from the first double-blind IMPinjection up to 21 days after the last double-blind IMP injection or upto the upper limit of the Week 24 analysis window, whichever came first.All calculated LDL-C values (scheduled or unscheduled, fasting or notfasting) may be used to provide a value for the primary efficacyendpoint if appropriate according to above definition.

The key secondary efficacy endpoints were: 1) The percent change incalculated LDL-C from baseline to Week 12: similar definition and rulesas for primary efficacy endpoint, except that the calculated LDL-C atWeek 12 was the LDL-C level obtained within the Week 12 analysis windowand during the 12-week efficacy period. The 12-week efficacy period wasdefined as the time from the first double-blind IMP injection up to theVisit 6 re-supply IVRS contact or up to 21 days after the lastdouble-blind IMP injection, whichever came first. Blood samplingcollected the day of the Visit 6 re-supply IVRS contact was consideredas before titration; 2) the percent change in Apo B from baseline toWeek 24. Same definition and rules as for the primary endpoint; 3) thepercent change in non-HDL-C from baseline to Week 24. Same definitionand rules as for the primary endpoint; 4) the percent change in total-Cfrom baseline to Week 24. Same definition and rules as for the primaryendpoint; 5) the percent change in Apo B from baseline to Week 12. Samedefinition and rules as for the percent change in calculated LDL-C frombaseline to Week 12; 6) the percent change in non-HDL-C from baseline toWeek 12. Same definition and rules as for the percent change incalculated LDL-C from baseline to Week 12; 7) the percent change intotal-C from baseline to Week 12. Same definition and rules as for thepercent change in calculated LDL-C from baseline to Week 12; 8) thepercent change in calculated LDL-C from baseline to Week 52. Definitionsand rules were similar to the ones used for the primary endpointreplacing Week 24 by Week 52. The 52-week efficacy period was defined asthe time from the first double-blind IMP up to 21 days after the lastdouble-blind IMP injection, or up to the upper limit of the Week 52analysis window whichever came first; 9) the proportion of patientsreaching LDL-C goal at Week 24, i.e. LDL-C<70 mg/dL (1.81 mmol/L) incase of prior CVD or <100 mg/dL (2.59 mmol/L) for patients without CVD,defined as: (number of patients whose calculated LDL-C value at Week 24reach LDL-C goal/number of patients in the mITT population)*100, usingdefinition and rules used for the primary endpoint; 10) the percentchange in Lp(a) from baseline to Week 24. Same definition and rules asfor the primary endpoint; 11) the percent change in HDL-C from baselineto Week 24. Same definition and rules as for the primary endpoint; 12)the percent change in HDL-C from baseline to Week 12. Same definitionand rules as for the percent change in calculated LDL-C from baseline toWeek 12; 13) the percent change in Lp(a) from baseline to Week 12. Samedefinition and rules as for the percent change in calculated LDL-C frombaseline to Week 12; 14) the percent change in fasting TG from baselineto Week 24. Same definition and rules as for the primary endpoint; 15)the percent change in fasting TG from baseline to Week 12. Samedefinition and rules as for the percent change in calculated LDL-C frombaseline to Week 12; 16) the percent change in Apo A-1 from baseline toWeek 24. Same definition and rules as for the primary endpoint; 17) thepercent change in Apo A-1 from baseline to Week 12. Same definition andrules as for the percent change in calculated LDL-C from baseline toWeek 12.

Other secondary efficacy endpoints were: 1) the percent change incalculated LDL-C from baseline to Week 78: Definitions and rules weresimilar to the ones used for the primary endpoint replacing Week 24 byWeek 78; 2) the proportion of patients reaching LDL-C goal at Weeks 12,52 and 78, i.e., LDL-C<70 mg/dL (1.81 mmol/L) in case of prior CVD or<100 mg/dL (2.59 mmol/L) for patients without prior CVD; 3) theproportion of patients reaching LDL C<100 mg/dL (2.59 mmol/L) at Week24; 4) the proportion of patients reaching LDL-C<100 mg/dL (2.59 mmol/L)at Week 12; 5) the proportion of patients reaching LDL-C<70 mg/dL (1.81mmol/L) at Week 24; 6) the proportion of patients reaching LDL-C<70mg/dL (1.81 mmol/L) at Week 12; 7) the absolute change in calculatedLDL-C (mg/dL and mmol/L) from baseline to Weeks 12, 24, 52 and 78; 8)the percent change in Apo B, non-HDL-C, total-C, Lp (a), HDL-C, fastingTG, and Apo A-1 from baseline to Week 52 and 78; 9) the change in ratioApo B/Apo A-1 from baseline to Weeks 12, 24, 52 and 78; 10) theproportion of patients with Apo B<80 mg/dL (0.8 g/L) at Weeks 12, 24, 52and 78; 11) the proportion of patients with non-HDL-C<100 mg/dL at Weeks12, 24, 52 and 78; 12) the proportion of patients with calculatedLDL-C<70 mg/dL (1.81 mmol/L) and/or ≥50% reduction in calculated LDL-C(if calculated LDL-C≥70 mg/dL [1.81 mmol/L]) at Weeks 12, 24, 52 and 78.

Total-C, HDL-C, TG, Apo B, Apo A-1, and Lp (a) were directly measured bythe Central Laboratory. LDL-C was calculated using the Friedewaldformula at all visits (except Week-1 and Follow Up visit). If TG valuesexceeded 400 mg/dL (4.52 mmol/L) then the central lab reflexivelymeasured (via the beta quantification method) the LDL-C rather thancalculating it. Non-HDL-C was calculated by subtracting HDL-C from thetotal-C. Ratio Apo B/Apo A-1 was calculated.

The clinical laboratory data consisted of urinalysis, hematology (redblood cell count, hemoglobin, red blood cell distribution width (RDVV),reticulocyte count, hematocrit, platelets, white blood cell count withdifferential blood count), standard chemistry (glucose, sodium,potassium, chloride, bicarbonate, calcium, phosphorous, urea nitrogen,creatinine, uric acid, total protein, LDH, albumin, γ GlutamylTransferase [γGT]), Hepatitis C antibody, liver panel (ALT, AST, ALP,and total bilirubin), and CPK.

Vital signs included: heart rate, systolic and diastolic blood pressurein sitting position.

Other endpoints included: anti-Alirocumab antibody assessments, hs-CRP,HbA_(1c), EQ-5D Questionnaire, and pharmacogenetic samples.

Anti-Alirocumab antibodies included the antibody status(positive/negative) and antibody titers. Serum samples foranti-Alirocumab antibody determination were drawn periodicallythroughout the study. The first scheduled sample at randomization visitwas obtained before IMP injection (predose). Patients who had titers ator above 240 for anti-Alirocumab antibodies at the follow-up visit hadadditional antibody sample(s) at 6 to 12 months after the last dose, andthereafter about every 3 to 6 months until titer returned below 240.Anti-Alirocumab antibody samples were analyzed using a validatednon-quantitative, titer-based bridging immunoassay. It involved aninitial screen, a confirmation assay based on drug specificity, and ameasurement of the titer of anti-Alirocumab antibodies in the sample.The lower limit of detection was approximately 1.5 ng/mL. Samples thatwere positive in the ADA assay were assessed for neutralizing antibodiesusing a validated, non-quantitative, competitive ligand binding assay.The lower limit of detection based on a monoclonal positive controlneutralizing antibody was 390 ng/mL.

The percent change in hs-CRP from baseline to Week 24, 52 and 78.

The absolute change in HbA1c (%) from baseline to Week 24, 52 and 78.

EQ-5D is a standardized measure of health status developed by theEuroQol Group in order to provide a simple, generic measure of healthfor clinical and economic appraisal. The EQ-5D as a measure ofhealth-related quality of life defines health in terms of 5 dimensions:mobility, self-care, usual activities, pain/discomfort,anxiety/depression. Each dimension can take one of three responses (3ordinal levels of severity): ‘no problem’ (1), “some problems” (2),“severe problems” (3). Overall health state was defined as a 5-digitnumber. Health states defined by the 5-dimensional classification can beconverted into corresponding index scores that quantify health status,where 0 represents ‘death’ and 1 represents “perfect health”.

Study Procedures

For all visits after Day 1/Week 0 (randomization visit), a timeframe ofa certain number of days was allowed. The window period for visits atWeeks 12 and 24 was ±3 days, at Week 52 and 78 was ±5 days, and for allother site visits it was ±7 days during the double-blind treatmentperiod, and follow-up period. A window period of +3 days was allowed forthe randomization visit (Day 1/Week 0) and ±7 days for the injectiontraining visit at screening (Week-1).

The blood sampling for determination of lipid parameters (i.e. total-C,LDL-C, HDL-C, TG, non-HDL-C, Apo B, Apo A-1, ratio Apo B/Apo A-1, Lp[a]) was to be performed in the morning, in fasting condition (i.e.overnight, at least 10-12 hours fast and refrain from smoking) for allsite visits throughout the study. Alcohol consumption within 48 hoursand intense physical exercise within 24 hours preceding the bloodsampling were discouraged. Note: if the patient was not in fastingconditions, the blood sample was not be collected and a new appointmentwas given the day after (or as close as possible to this date) to thepatient with instruction to be fasted (see above conditions).

Only patients who met the inclusion criteria were screened. Thescreening period took place up to 3 weeks or 21 days (and as short aspossible, upon receipt of laboratory eligibility criteria) prior torandomization/Day 1 visit. The first screening visit (Week-3) took placefrom 21 to 8 days before the randomization visit. If it was planned tohave another designated person administer the injections to the patientduring the study, then this person should have been present at theinjection training visit (Week-1).

The following visits were scheduled: Screening Visit (Visit1/Week-3/Day−21 up to −8); Screening (Visit2/Week-1/Day −7±7); Randomization visit(Visit 3/Week 0/Day 1+3); Visit 4/Week 4/Day 29±7):; Visit 5/Week 8/Day57±7); Visit 6/Week 12/Day 85±3; Visit 7/Week 16/Day 113±7): Visit8/Week 24/Day 169±3; Visit 9/Week 36/Day 253±7; Visit 10/Week 52/Month12/Day 365±5; Visit 11/Week 64/Day 449±7; Visit 12/Week 78/Month 18/Day547±5 (end of treatment visit); and Visit 13/Week 86/Day 603±7 (followup visit).

Safety

Monitored safety events were the occurrence of treatment emergentadverse events (TEAEs) reported by the patient or noted by theinvestigator, serious adverse events (SAEs), TEAEs leading to treatmentdiscontinuation, AEs of special interest (local Injection sitereactions, allergic events, selected neurological events andcardiovascular events with adjudication result), occurrence of PCSA(potentially clinically significant abnormalities) in laboratoryparameters, specific analysis for diabetes or impaired glucose controland patients with 2 consecutives LDL-C<25 mg/dL.

Statistical Methods Sample Size Determination:

A total sample size of 45 patients (30 in alirocumab and 15 in placebo)had 95% power to detect a difference in mean percent change in LDL-C of30% with a 0.05 two-sided significance level and assuming a commonstandard deviation of 25%, and all these 45 patients having an evaluableprimary endpoint. A final total sample size of 105 patients with arandomization ratio 2:1 (alirocumab 70:placebo 35) has been selected inorder to provide at least 50 patients exposed to alirocumab for 12months at the first step analysis and assuming a drop-out rate of 10%over the first 3-month period and a drop-out rate of 20% over the3-12-month period.

Timing of Analyses:

The first step analysis included efficacy endpoints up to Week 52 (finalefficacy analysis) and interim safety analysis, which was performed onall safety data up to the common study cut-off date (last patient Week52 visit). Analysis of lipid data beyond Week 52 was descriptive.Results of the first step analysis are presented herein.

Second step (final) analysis will be conducted at the end of the studyand will consist in the final analysis of efficacy endpoints up to Week78 and final safety analysis.

Analysis Populations:

The primary efficacy analysis population was the intent-to-treat (ITT)population, defined as all randomized patients who had an evaluableprimary efficacy endpoint, that is, those with an available baselinecalculated LDL-C value, and at least one available calculated LDL-Cvalue within one of the analysis windows up to Week 24 (including allcalculated LDL-C on-treatment and off-treatment).

The secondary efficacy analysis population was the modifiedintent-to-treat (mITT) population, defined as all randomized patientswho took at least one dose or part of a dose of the double-blindinvestigational medicinal product (IMP) and who had an availablecalculated LDL-C value at baseline and at least one within one of theanalysis windows up to Week 24 during the efficacy treatment period. Theefficacy treatment period was defined as the time from the firstdouble-blind IMP administration up to 21 days after the lastdouble-blind injection.

The safety population included all randomized patients who received atleast one dose or part of a dose of the double-blind IMP.

Efficacy Analyses:

Primary analyses of efficacy endpoints were conducted using an ITTapproach (based on the ITT population defined above), including alllipid data, regardless of whether the patient was continuing therapy ornot. This corresponds to ITT estimands, defined for primary and keysecondary endpoints. In addition, analyses were also conducted using anon-treatment approach (based on the mITT population defined above),including lipid data collected during the efficacy treatment period.This corresponds to on-treatment estimands of key secondary endpoints.

The ITT approach analyzed all patients, irrespective of their adherenceto the treatment; it assessed the benefit of the treatment strategy andreflected as much as possible the effect in a population of patients.The on-treatment approach analyzed the effect of treatment, restrictedto the period during which patients actually received the treatment. Itassessed the benefit that a treatment would achieve in patients adherentto treatment up to the considered time point.

Efficacy analyses were performed according to treatment as-randomized.

All measurements, scheduled or unscheduled, fasting or not fasting, wereassigned to analysis windows in order to provide an assessment for Week4 to Week 78 time points.

With regards to the primary efficacy analysis (ITT approach), thepercent change in calculated LDL-C from baseline to Week 24 was analyzedusing a mixed-effect model with repeated measures (MMRM) approach. Allpost-baseline data available from Week 4 to Week 52 analysis windowswere used and missing data were accounted for by the MMRM. The modelincluded the fixed categorical effects of treatment group (placeboversus alirocumab), randomization strata (as per IVRS), time point (Week4 to Week 52), treatment-by-time point interaction and strata-by-timepoint interaction, as well as, the continuous fixed covariates ofbaseline LDL-C value and baseline value-by-time-point interaction. Thismodel provided baseline adjusted least-squares means (LSmeans) estimatesat Week 24 for both treatment groups with their corresponding 95%confidence interval. To compare the alirocumab to the placebo group, anappropriate statement was used to test the differences of theseestimates at the 5% alpha level.

A hierarchical procedure has been defined to test key secondaryendpoints while controlling for multiplicity (using above order of keysecondary endpoints). The first key secondary endpoint was the percentchange in calculated LDL-C from baseline to Week 24 using anon-treatment approach.

Continuous secondary variables anticipated to have a normal distribution(i.e., lipids other than TG and Lp(a)) were analyzed using the same MMRMmodel as for the primary endpoint. Continuous endpoints anticipated tohave a non-normal distribution (i.e., TG and Lp(a)) were analyzed usingmultiple imputation approach for handling of missing values followed byrobust regression model with endpoint of interest as response variableusing M-estimation (using SAS ROBUSTREG procedure) with treatment group,randomization strata (as per IVRS) and corresponding baseline value(s)as effects to compare treatment effects. Combined estimate for mean inboth treatment groups, as well as the differences of these estimates,with their corresponding SEs, 95% CIs and p-value were provided (throughSAS MIANALYZE procedure).

Binary secondary efficacy endpoints were analyzed using multipleimputation approach for handling of missing values followed bystratified logistic regression with treatment group as main effect andcorresponding baseline value(s) as covariate, stratified byrandomization factors (as per IVRS). Combined estimates of odds ratioversus placebo, 95% CI, and p-value were provided (through SAS MIANALYZEprocedure).

Safety Analyses:

Safety analyses were descriptive, performed on the safety populationaccording to treatment actually received. The safety analysis focused onthe TEAE period defined as the time from the first dose of double-blindup to 70 days after the last double-blind injection. TEAE whichdeveloped, worsened or became serious or PCSA occurring after thepatient inclusion in the open-label extension study (LTS13643) were notconsidered in the TEAE period. TEAE period was truncated at the commonstudy cut-off date.

Results Study Patients Patient Accountability

Of the 107 randomized patients (72 and 35 patients in the alirocumab andthe placebo groups, respectively), one patient in the alirocumab groupdid not have any baseline calculated LDL-C value and was therefore notincluded in the ITT and mITT populations.

TABLE 26 Analysis populations Alirocumab Placebo 150 Q2W All Randomizedpopulation 35 (100%) 72 (100%)  107 (100%)  Efficacy populationsIntent-to-Treat (ITT) 35 (100%) 71 (98.6%) 106 (99.1%) ModifiedIntent-to-Treat (mITT) 35 (100%) 71 (98.6%) 106 (99.1%) Safetypopulation 35 72 107 Note: The safety population patients are tabulatedaccording to treatment actually received (as treated). For the otherpopulations, patients are tabulated according to their randomizedtreatment.

Study Disposition

Study disposition, exposure, efficacy and safety analyses were assessedusing all data up to the common cut-off date of the study (defined asthe date of last patient's Week 52 visit). Therefore, this first stepanalysis includes efficacy data up to Week 52 and safety data beyondWeek 52 and up to Week 78 or Follow-up visit for some patients. Patientdisposition is shown in FIG. 12.

In this study, one site with 7 patients randomized and a second sitewith 6 patients randomized were identified with serious GCPnon-compliance, and the sites were closed. For the first closed site,one of the key findings was related to IMP injections reported as havingbeen received by some patients whereas corresponding kits werediscovered in the fridge. The reporting of these injections wascorrected in the database but other issues on injections could not beexcluded. For the second site, persistent concerns with the conduct ofthe study and associated documentation related to the study wereobserved during routine monitoring.

Among these 13 patients, one was still ongoing at the cut-off date, onediscontinued for adverse event, one patient moved, 3 patientsdiscontinued for poor compliance to protocol and 7 patients discontinueddue to decision of site closure.

There were in total 10 (9.3%) randomized patients who completed the 78weeks double-blind study treatment period and 76 (71.0%) randomizedpatients with treatment ongoing at the time of the first-step analysiscut-off date. The double-blind IMP was prematurely discontinued beforeWeek 78 for 6 (17.1%) patients in the placebo group and 15 (20.8%)patients in the alirocumab group. All these patients actuallyprematurely discontinued before Week 52. The main reasons for studytreatment discontinuation were “other reasons”, poor compliance andadverse events. These “other reasons” included the 7 patients whodiscontinued due to the decision of site closure as mentioned above, 1patient withdrawal not otherwise specified, 1 patient withdrew due tocholesterol results obtained independently and 1 patient moved.

In this first step analysis, final results are available for primaryefficacy endpoint at Week 24 and key secondary efficacy endpointsassessed at Week 12, Week 24 and Week 52. The following table providesthe availability of LDL-C over time. At Week 24, the primary efficacyendpoint was available for 33 (94.3%) in the placebo and 63 (88.7%) inthe alirocumab group.

TABLE 27 Calculated LDL-C availability over time - ITT populationPlacebo Alirocumab 150 Q2W (N = 35) (N = 71) On- Post- Post- Calculatedtreatment treatment Missing On-treatment treatment Missing LDL-C valuevalue value value value value Week 4 31 (88.6%) 0 4 (11.4%) 67 (94.4%) 04 (5.6%) Week 8 34 (97.1%) 0 1 (2.9%) 66 (93.0%) 0 5 (7.0%) Week 12 33(94.3%) 0 2 (5.7%) 68 (95.8%) 0 3 (4.2%) Week 16 28 (80.0%) 0 7 (20.0%)66 (93.0%) 0 5 (7.0%) Week 24 33 (94.3%) 0 2 (5.7%) 62 (87.3%) 1 (1.4%)8 (11.3%) Week 36 30 (85.7%) 1 (2.9%) 4 (11.4%) 60 (84.5%) 3 (4.2%) 8(11.3%) Week 52 27 (77.1%) 0 8 (22.9%) 52 (73.2%) 2 (2.8%) 17 (23.9%)

The primary endpoint was missing for 10 patients at Week 24 (2 and 8patients in placebo and alirocumab groups, respectively). At the Week 24visit (as per CRF monitoring), the reasons for missingness were asfollows: 3 samples not done due to earlier study discontinuation; 3samples done outside analysis time window; 2 samples not done due toWeek 24 visit not done; and 2 samples available but measurement couldnot be done (lipemia, insufficient quantity, TGs>400 mg/dL[>4.52mmol/L], sample lost, etc.).

The higher number of missing data at Week 52 is mainly due to thedecision to close the two sites due to serious GCP non-compliance.

The LDL-C endpoint at Week 52 was missing for 25 out of 106 patients.The reasons for missing results were as follows: 17 samples not done dueto earlier study discontinuation including 11 patients from the twoclosed sites; 3 samples done outside analysis time window; 1 sample notdone due to Week 52 not done; 1 missing sample while visit Week 52 wasdone; and 3 samples available but measurement could not be done (TGs>400mg/dL[>4.52 mmol/L] and hemolysis).

Demographics and Baseline Characteristics Summary PopulationCharacteristics:

107 HeFH patients diagnosed by genotyping (17.8%) and WHO/Dutch LipidNetwork criteria (score of >8 points) or Simon Broome criteria fordefinite FH (82.2%) were randomized 2:1 to alirocumab (150 mg Q2W) orplacebo.

Demographics characteristics, disease characteristics and lipidparameters at baseline were generally similar in the alirocumab group ascompared to the placebo group: diagnosis of HeFH through genotyping inthe alirocumab (19.4%) vs the placebo group (14.3%); diagnosis of HeFHthrough clinical criteria in the alirocumab (80.6%) vs the placebo group(85.7%); a mean age (SD) in the alirocumab group of 49.8 years (14.2) vsa mean age of the placebo group of 52.1 years (11.2); percentage ofwhite race in the alirocumab (88.9%) vs the placebo (85.7%) group; and amean BMI (SD) in the alirocumab group of 28.8 kg/m² (5.2) vs a mean BMIin the placebo group of 28.9 kg/m² (4.2). Some imbalances were noted dueto the small sample size of the study: a higher proportion of femalepatients in the alirocumab group (51.4%) vs the placebo group (37.1%);more recent hypercholesterolemia diagnosis in the alirocumab group(median of 9.8 years) vs the placebo group (median of 17.4 years); alower proportion of patients considered as very high CV risk in thealirocumab group (52.8%) than in the placebo group (65.7%) mainly drivenby a medical history of coronary revascularization procedure; and alower proportion of patients received ezetimibe at randomization in thealirocumab group (19.4%) than in the placebo group (34.3%). Thecardiovascular history and risk factors of patients in both thealirocumab and placebo groups are shown in Table 28.

TABLE 28 Cardiovascular history and risk factors All patients onbackground of maximally Alirocumab tolerated statin ± Placebo 150 Q2WAll other LLT (N = 35) (N = 72) (N = 107) CHD history, % (n) 43.1% (31)62.9% (22) 49.5% (53) Acute MI, % (n) 22.1% (16) 22.9% (8) 22.4% (24)Silent MI, % (n) 1.4% (1) 0 0.9% (1) Unstable angina, % (n) 9.7% (7)17.1% (6) 12.1% (13) Coronary 15.3% (11) 40.0% (14) 23.4% (25)revascularization procedures, % (n) Other clinically 27.8% (20) 28.6%(10) 28.0% (30) significant CHD, % (n) Current smoker, % (n) 16.7% (12)25.7% (9) 19.6% (21) Hypertension, % (n) 55.6% (40) 60.0% (21) 57.0%(61) Type 2 diabetes, % (n) 12.5% (9) 17.1% (6) 14.0% (15)

At randomization, all patients were treated with a statin, 72.9%receiving high intensity statin (atorvastatin 40 to 80 mg daily orrosuvastatin 20 to 40 mg daily) and 6.5% receiving simvastatin 80 mg. Inaddition to the statin, 19.4% and 34.3% of patients were receivingezetimibe in the alirocumab and placebo groups respectively. Table 30shows the background lipid modifiying therapies (LMTs) of the alirocumaband placebo treated populations at randomization as well as those of thetotal randomized population.

Table 31 shows the lipid efficacy parameters at baseline of thealirocumab and placebo treated populations as well as the totalrandomized population. Mean (SD) calculated LDL-C at baseline was 197.8(53.4) mg/dL (5.123 (1.38) mmol/L). Mean (SD) non-HDL-C at baseline was226.4 (55.3) mg/dL. Mean (SD) Total-C at baseline was 274.4 (54.0)mg/dL. Mean (SD) HDL-C at baseline was 48.1 (13.3) mg/dL. The mean (SD)Total-C/HDL-C ratio at baseline was 6.135 (2.119). Mean (SD) fastingtriglycerides (TGs) at baseline was 149.8 (86.6) mg/dL. Mean (SD)Lipoprotein-(a) at baseline was 41.2 (46.6) mg/dL. Mean (SD) Apo-B atbaseline was 140.9 (31.0) mg/dL. Mean (SD) Apo-Al at baseline was 137.5(23.3) mg/dL. The mean (SD) Apo-B/Apo-A1 ratio at baseline was 1.061(0.323) mg/dL.

Exposure to injections was similar across treatment groups with a meanexposure of 60.7 weeks in placebo group and 58.3 weeks in alirocumabgroup.

TABLE 29 Disease characteristics and other relevant baseline data -Randomized population Alirocumab Placebo 150 Q2W All (N = 35) (N = 72)(N = 107) Type of hypercholesterolemia Heterozygous Familial 35 (100%)72 (100%) 107 (100%) Hypercholesterolemia (heFH) Non-Familial  0  0 0Hypercholesterolemia (non-FH) Time from hypercholesterolemia diagnosis(years) Number 35 72 107  Mean (SD) 16.41 (12.62) 11.48 (10.48) 13.09(11.41) Median   17.42    9.76   11.70 Min:Max 0.0:42.8 0.0:39.90.0:42.8 Confirmation of diagnosis By genotyping 5 (14.3%) 14 (19.4%) 19(17.8%) By WHO/Simon 30 (85.7%) 58 (80.6%) 88 (82.2%) Broome^(a) ^(a)forheFH diagnosis not confirmed by genotyping.

TABLE 30 Background LMT at randomization - Randomized populationAlirocumab Placebo 150 Q2W All (N = 35) (N = 72) (N = 107) Any statin 35(100%) 72 (100%) 107 (100%) Taking high dose statin 28 (80.0%) 57(79.2%) 85 (79.4%) Taking high intensity statin 25 (71.4%) 53 (73.6%) 78(72.9%) Atorvastatin daily dose 10 (28.6%) 22 (30.6%) 32 (29.9%) (mg) 100 0 0 20 0 0 0 40 3 (8.6%) 10 (13.9%) 13 (12.1%) 80 7 (20.0%) 11 (15.3%)18 (16.8%) Other doses 0 1 (1.4%) 1 (0.9%) Rosuvastatin daily dose 16(45.7%) 33 (45.8%) 49 (45.8%) (mg)  5 1 (2.9%) 2 (2.8%) 3 (2.8%) 10 0 00 20 3 (8.6%) 8 (11.1%) 11 (10.3%) 40 12 (34.3%) 23 (31.9%) 35 (32.7%)Other doses 0 0 0 Simvastatin daily dose (mg) 10 (28.6%) 19 (26.4%) 29(27.1%) 10 1 (2.9%) 4 (5.6%) 5 (4.7%) 20 1 (2.9%) 2 (2.8%) 3 (2.8%) 40 5(14.3%) 9 (12.5%) 14 (13.1%) 80 3 (8.6%) 4 (5.6%) 7 (6.5%) Other doses 00 0 Any LMT other than 13 (37.1%) 16 (22.2%) 29 (27.1%) statins^(a) AnyLMT other than 12 (34.3%) 16 (22.2%) 28 (26.2%) nutraceuticals Ezetimibe12 (34.3%) 14 (19.4%) 26 (24.3%) Nutraceuticals 1 (2.9%) 0 1 (0.9%)^(a)in combination with statins or not. High intensity statincorresponds to atorvastatin 40 to 80 mg daily or rosuvastatin 20 to 40mg daily. High dose statin corresponds to atorvastatin 40 to 80 mgdaily, rosuvastatin 20 to 40 mg daily, or simvastatin 80 mg daily.

TABLE 31 Lipid efficacy parameters at baseline - Quantitative summary inconventional units - Randomized population Alirocumab Placebo 150 Q2WAll (N = 35) (N = 72) (N = 107) Calculated LDL-C (mg/dL) Number 35 71106 Mean (SD) 201.0 (43.4) 196.3 (57.9) 197.8 (53.4) Median  201.0 180.0   181.0 Q1:Q3 166.0:240.0 165.0:224.0 165.0:224.0 Min:Max 137:279 89:402  89:402 Non-HDL-C (mg/dL) Number 35 72 107 Mean (SD) 231.5(47.6) 223.9 (58.8) 226.4 (55.3) Median  226.0  204.0   209.0 Q1:Q3194.0:274.0 189.5:251.0 191.0:260.0 Min:Max 153:326 117:419 117:419Total-C (mg/dL) Number 35 72 107 Mean (SD) 276.4 (46.8) 273.5 (57.5)274.4 (54.0) Median  272.0  256.0   259.0 Q1:Q3 237.0:313.0 242.5:300.5241.0:310.0 Min:Max 202:364 171:458 171:458 HDL-C (mg/dL) Number 35 72107 Mean (SD) 44.9 (11.3) 49.6 (14.0) 48.1 (13.3) Median   42.0   45.5  45.0 Q1:Q3 39.0:51.0 39.5:57.5 39.0:55.0 Min:Max 24:72 28:84 24:84Fasting TGs (mg/dL) Number 35 72 107 Mean (SD) 156.3 (89.3) 146.6 (85.6)149.8 (86.6) Median  122.0  131.5   129.0 Q1:Q3  95.0:193.0  87.5:160.5 94.0:171.0 Min:Max  62:455  40:512  40:512 Lipoprotein- (a)(mg/dL)Number 34 71 105 Mean (SD) 46.2 (50.3) 38.8 (44.9) 41.2 (46.6) Median  30.0   22.0   26.0 Q1:Q3 11.0:42.0  8.0:50.0 10.0:48.0 Min:Max  2:201 2:189  2:201 Apo-B (mg/dL) Number 34 71 105 Mean (SD) 146.6 (28.3)138.2 (32.0) 140.9 (31.0) Median  143.0  130.0   134.0 Q1:Q3 121.0:173.0118.0:154.0 119.0:158.0 Min:Max  99:208  81:255  81:255 Apo-A1 (mg/dL)Number 34 71 105 Mean (SD) 131.5 (19.2) 140.3 (24.6) 137.5 (23.3) Median 127.5  137.0   134.0 Q1:Q3 120.0:142.0 122.0:155.0 122.0:151.0 Min:Max 97:181  97:211  97:211 Apo-B/Apo-A1 (ratio) Number 34 71 105 Mean (SD)1.141 (0.287) 1.023 (0.334) 1.061 (0.323) Median    1.170    0.950    1.020 Q1:Q3 0.900:1.300 0.800:1.170 0.850:1.230 Min:Max 0.58:1.860.49:2.32 0.49:2.32 Total-C/HDL-C (ratio) Number 35 72 107 Mean (SD)6.540 (1.986) 5.938 (2.167) 6.135 (2.119) Median    6.417    5.647    5.863 Q1:Q3 4.936:7.600 4.399:6.878 4.545:7.370 Min:Max  3.29:11.19 2.92:13.48  2.92:13.48

Dosage and Duration

Exposure to injections was similar across treatment groups with a meanexposure of 60.7 weeks in the placebo group and 58.3 weeks in thealirocumab group. Duration of exposure for injection could not becalculated for 1 patient in alirocumab group due to unknown lastinjection date.

Efficacy Primary Efficacy Endpoint

The ITT analysis includes all calculated LDL-C values collectedon-treatment and off-treatment up to Week 52. The primary endpoint(percent change in calculated LDL-C from baseline to Week 24) analysisis provided based on a MMRM model on the ITT population, using LS meansestimates at Week 24. Nine (11.3%) patients in the alirocumab group and2 (5.7%) patients in the placebo group did not have a calculated LDL-Cvalue at Week 24. These missing values were accounted for by the MMRMmodel.

Results of the primary endpoint analysis are presented in Table 32, inmmol/L and mg/dL.

Primary Efficacy Analysis

A statistically significant decrease in percent change in LDL-C frombaseline to Week 24 was observed in the alirocumab group (LS mean versusbaseline−45.7%) compared to the placebo group (LS mean versusbaseline−6.6%) (LS mean difference vs. placebo (SE) of −39.1% (6.0%),p<0.0001) (see Table 31). This represents an absolute reduction (SD) of−90.8 (6.7) mg/dL in the alirocumab group and −15.5 (9.5) mg/dL in theplacebo group (see Table 33). Percent change from baseline to Week 24 inLDL-C by individual patients are set forth in FIG. 13. All patients wereon a background statin (at the maximum tolerated level). A subset ofpatients also received a further lipid lowering therapy.

In the alirocumab group, LDL-C reduction from baseline was observed fromWeek 4 to Week 52 (see FIG. 7, FIGS. 14A-14B and Table 33). A slightdecrease in LDL-C reduction over time was observed in the alirocumabgroup (LS mean versus baseline at Week 52 of −42.1 versus −45.7 at Week24), although the overall amount of the decrease stayed the same (75mg/dL; see FIGS. 14A-14B). Furthermore, significant numbers of patientson alirocumab achieved LDL-C levels of <100 mg/dL (57% vs 11% of placebopatients) and<70 mg/dL (<1.81 mmol/L; 32% vs 3% of placebo patients) atWeek 24 despite baseline LDL-C levels of >190 mg/dL (mean (SD) baselinecalculated LDL-C 196.3 (57.9) mg/dL for alirocumab group; 201 (43.4)mg/dL for placebo group). At week 12, 31.0% of alirocumab group patients(vs. 0.0% of placebo group; ITT analysis) reached calculated LDL-Clevels of <70 mg/dL (<1.81 mmol/L). Similarly, at Week 52, 31.0% ofalirocumab group patients (vs 5.7% of placebo group; ITT analysis)reached calculated LDL-C levels of <70 mg/dL (<1.81 mmol/L).

A sensitivity analysis of the primary efficacy endpoint was performedexcluding 13 patients from 2 sites with serious GCP non compliance. Thedecrease in percent change in LDL-C from baseline to Week 24 was stillstatistically significant in the alirocumab group (LS mean versusbaseline−50.3%) compared to the placebo group (LS mean versusbaseline−2.3%) (LS mean difference vs. placebo (SE) of −48.0% (5.8%),p<0.0001) (see Table 34).

TABLE 32 Percent change from baseline in calculated LDL-C at Week 24:MMRM - ITT analysis - ITT population Alirocumab Calculated LDL Placebo150 Q2W Cholesterol (N = 35) (N = 71) Baseline (mmol/L) Number 35 71Mean (SD) 5.205 (1.125) 5.083 (1.499) Median    5.206    4.662 Min:Max3.55:7.23 2.31:10.41 Baseline (mg/dL) Number 35 71 Mean (SD) 201.0(43.4) 196.3 (57.9) Median  201.0  180.0 Min:Max 137:279 89:402 Week 24percent change from baseline (%) LS Mean (SE) −6.6 (4.9) −45.7 (3.5) LSmean difference (SE) vs placebo −39.1 (6.0) 95% CI (−51.1 to −27.1)p-value vs placebo     <0.0001* Note: Least-squares (LS) means, standarderrors (SE) and p-value taken from MMRM (mixed-effect model withrepeated measures) analysis. The model includes the fixed categoricaleffects of treatment group, randomization strata as per IVRS, timepoint, treatment-by-time point and strata-by-time point interaction, aswell as the continuous fixed covariates of baseline calculated LDL-Cvalue and baseline calculated LDL-C value-by-time point interaction MMRMmodel and baseline description run on patients with a baseline value anda post-baseline value in at least one of the analysis windows used inthe model. The p-value is followed by a ‘*’ if statistically significantaccording to the fixed hierarchical approach used to ensure a strongcontrol of the overall type-I error rate at the 0.05 level

TABLE 33 Calculated LDL-C overtime - ITT analysis - ITT populationPlacebo Alirocumab 150 Q2W (N = 35) (N = 71) Percent Percent Changechange Change change Calculated from from from from LDL-C Value baselinebaseline Value baseline baseline LS Mean (SE) (mmol/L) Baseline ^(a)5.205 (0.190) NA NA 5.083 (0.178) NA NA Week 4 4.537 (0.221) −0.586(0.221) −11.5 (4.1) 2.522 (0.154) −2.601 (0.154) −52.9 (2.8) Week 84.435 (0.229) −0.688 (0.229) −12.4 (4.3) 2.647 (0.161) −2.477 (0.161)−48.6 (3.1) Week 12 4.702 (0.234) −0.422 (0.234) −6.6 (4.6) 2.692(0.164) −2.432 (0.164) −46.9 (3.2) Week 16 4.779 (0.235) −0.344 (0.235)−6.1 (4.8) 2.633 (0.161) −2.490 (0.161) −48.0 (3.3) Week 24 4.722(0.246) −0.401 (0.246) −6.6 (4.9) 2.771 (0.174) −2.352 (0.174) −45.7(3.5) Week 36 4.666 (0.251) −0.457 (0.251) −8.9 (5.0) 2.832 (0.176)−2.292 (0.176) −44.0 (3.5) Week 52 4.862 (0.275) −0.262 (0.275) −3.0(5.9) 2.921 (0.197) −2.202 (0.197) −42.1 (4.2) Week 78 1.2 (6.4) −37.9(4.5) LS Mean (SE) (mg/dL) Baseline ^(a) 201.0 (7.3) NA NA 196.3 (6.9)NA NA Week 4 175.2 (8.5) −22.6 (8.5) −11.5 (4.1) 97.4 (5.9) −100.4 (5.9)−52.9 (2.8) Week 8 171.2 (8.8) −26.6 (8.8) −12.4 (4.3) 102.2 (6.2) −95.6(6.2) −48.6 (3.1) Week 12 181.5 (9.0) −16.3 (9.0) −6.6 (4.6) 103.9 (6.3)−93.9 (6.3) −46.9 (3.2) Week 16 184.5 (9.1) −13.3 (9.1) −6.1 (4.8) 101.7(6.2) −96.1 (6.2) −48.0 (3.3) Week 24 182.3 (9.5) −15.5 (9.5) −6.6 (4.9)107.0 (6.7) −90.8 (6.7) −45.7 (3.5) Week 36 180.2 (9.7) −17.7 (9.7) −8.9(5.0) 109.3 (6.8) −88.5 (6.8) −44.0 (3.5) Week 52 187.7 (10.6) −10.1(10.6) −3.0 (5.9) 112.8 (7.6) −85.0 (7.6) −42.1 (4.2) ^(a) Baseline isdescribed using means and standard errors. Note: Least-squares (LS)means, standard errors (SE) and p-value taken from MMRM (mixed-effectmodel with repeated measures) analysis. The model includes the fixedcategorical effects of treatment group, randomization strata as perIVRS, time point, treatment-by-time point interaction, strata-by-timepoint interaction, as well as the continuous fixed covariates ofbaseline LDL-C value and baseline LDL-C value-by-time point interactionMMRM model and baseline description run on patients with a baselinevalue and a post-baseline value in at least one of the analysis windowsused in the model.

Sensitivity Analysis of Primary Endpoint

TABLE 34 Percent change from baseline in calculated LDL-C at Week 24:MMRM - ITT analysis - ITT population excluding sites with serious GCPnon compliance Alirocumab Calculated LDL Placebo 150 Q2W Cholesterol (N= 31) (N = 62) Baseline (mmol/L) Number 31 62 Mean (SD) 5.310 (1.146)5.101 (1.460) Median    5.258    4.675 Min:Max 3.55:7.23 2.31:10.41Baseline (mg/dL) Number 31 62 Mean (SD) 205.0 (44.2) 197.0 (56.4) Median 203.0  180.5 Min:Max 137:279 89:402 Week 24 percent change frombaseline (%) LS Mean (SE) −2.3 (4.7) −50.3 (3.3) LS mean difference (SE)vs placebo −48.0 (5.8) 95% CI (−59.4 to −36.6) p-value vs placebo   <0.0001 Note: Least-squares (LS) means, standard errors (SE) andp-value taken from MMRM (mixed-effect model with repeated measures)analysis. The model includes the fixed categorical effects of treatmentgroup, randomization strata as per IVRS, time point, treatment-by-timepoint and strata-by-time point interaction, as well as the continuousfixed covariates of baseline calculated LDL-C value and baselinecalculated LDL-C value-by-time point interaction MMRM model and baselinedescription run on patients with a baseline value and a post-baselinevalue in at least one of the analysis windows used in the model. Thep-value is not adjusted for multiplicity and provided for descriptivepurpose only Note: Sites No. 643-710 and No. 840-743 were excluded fromanalysis

Key Secondary Efficacy Endpoints

The following table summarizes analysis results on key secondaryendpoints in the hierarchical order. All key secondary endpoints arestatistically significant according to the hierarchical testingprocedure up to Lp(a) endpoint at Week 24 (ITT estimand) included.

Statistically significance was not reached for HDL-C at Week 24 (ITTestimand) and therefore the testing procedure was stopped, p-values areprovided from this endpoint for descriptive purpose only.

TABLE 35 Endpoint Analysis Results P-value Calculated LDL-C - PercentOn-treatment LS mean difference vs. <0.0001 change from baseline to Weekplacebo of −38.9% 24 Calculated LDL-C - Percent ITT LS mean differencevs. <0.0001 change from baseline to Week placebo of −40.3% 12 CalculatedLDL-C - Percent On-treatment LS mean difference vs. <0.0001 change frombaseline to Week placebo of −40.3% 12 Apo-B - Percent change from ITT LSmean difference vs. <0.0001 baseline to Week 24 placebo of −30.3%Apo-B - Percent change from On-treatment LS mean difference vs. <0.0001baseline to Week 24 placebo of −30.2% Non-HDL-C - Percent change ITT LSmean difference vs. <0.0001 from baseline to Week 24 placebo of −35.8%Non-HDL-C - Percent change On-treatment LS mean difference vs. <0.0001from baseline to Week 24 placebo of −35.5% Total-C - Percent change fromITT LS mean difference vs. <0.0001 baseline to Week 24 placebo of −28.4%Apo-B - Percent change from ITT LS mean difference vs. <0.0001 baselineto Week 12 placebo of −30.2% Non-HDL-C - Percent change ITT LS meandifference vs. <0.0001 from baseline to Week 12 placebo of −34.5%Total-C - Percent change from ITT LS mean difference vs. <0.0001baseline to Week 12 placebo of −27.8% Calculated LDL-C - Percent ITT LSmean difference vs. <0.0001 change from baseline to Week placebo of−39.1% 52 Proportion of very high CV ITT combined estimate for odds-0.0016 risk patients reaching ratio vs. placebo of 11.7 calculated LDL-C<70 mg/dL (1.81 mmol/L) or high CV risk patients reaching calculatedLDL-C <100 mg/dL (2.59 mmol/L) at Week 24 Proportion of very high CVOn-treatment combined estimate for odds- 0.0014 risk patients reachingratio vs. placebo of 11.9 calculated LDL-C <70 mg/dL (1.81 mmol/L) orhigh CV risk patients reaching calculated LDL-C <100 mg/dL (2.59 mmol/L)at Week 24 Lp(a) - Percent change from ITT combined estimate foradjusted 0.0164 baseline to Week 24 mean difference vs. placebo of−14.8% HDL-C - Percent change from ITT LS mean difference vs. placebo0.2745 baseline to Week 24 of 3.7% Fasting TGs - Percent change ITTcombined estimate for adjusted 0.1386 from baseline to Week 24 meandifference vs. placebo of −8.7%

The on-treatment analysis of the LDL-C percent change from baseline toWeek 24 shows very consistent results with the ITT analysis (LS meandifference vs. placebo of −38.9% in the on-treatment analysis versus−39.1% in the ITT analysis). Indeed, only 3 patients (2 in placebo and 1in alirocumab) had LDL-C values collected post-treatment (ie more than21 days after last injection) at Week 24.

The key secondary endpoints including Apo B, non-HDL-C, Total-C, Lp(a)at various time points as well as the proportion of patients reachingtheir LDL-C goals at Week 24 were statistically significant according tothe hierarchical testing procedure. Significant reductions were seen innon-HDL-C, Apo B, and Lp(a) levels at Week 24. The alirocumab vs placeboLS mean percent change from baseline to week 24 was −41.9 vs −6.2 fornon-HDL-C (p value<0.0001), −39.0 vs −8.7 for Apo B (p value<0.0001),and −23.5 vs −8.7 for Lp(a) (p value=0.0164).

The proportion of very high cardiovascular (CV) risk patients reachingcalculated LDL-C<70 mg/dL (1.81 mmol/L) or high CV risk patientsreaching calculated LDL-C<100 mg/dL (2.59 mmol/L) at Week 24 wassignificantly higher in the alirocumab than in the placebo group(combined estimate for proportion of 41.0% in the alirocumab group vs5.7% in the placebo group, p=0.0016).

Analyses performed with on-treatment approach were constitent with theseanalyses.

The differences in percent change in HDL-C and fasting TGs from baselineto Week 24 in the ITT analysis were non-statistically significant: HDL-Cat Week 24: LS mean versus baseline was +7.5% in the alirocumab groupand +3.9% in the placebo group (LS mean difference vs. placebo of +3.7%,p=0.2745); and Fasting TGs at Week 24: LS mean versus baseline was−10.5% in the alirocumab group and −1.1% in the placebo group (LS meandifference vs. placebo of −9.4%, p=0.1299).

Four (5.6%) patients experienced two consecutive calculated LDL-Cvalues<25 mg/dL. No particular safety concern has been observed in thesepatients.

Summary Safety Results:

The proportion of patients who experienced a treatment emergent adverseevent (TEAE) was lower in the alirocumab group (61.1%) compared toplacebo group (71.4%) in the present study. The proportion of patientswho experienced a serious TEAE was similar between treatment groups. Asimilar proportion of patients experienced TEAEs leading to treatmentdiscontinuation (1 patient (2.9%) and 3 patients (4.2%) in the placeboand alirocumab groups, respectively). These results are consistent withthe proportion of patients who have experienced TEAEs in previousalirocumab Phase 2/3 placebo-controlled studies (results from 2476 and1276 patients in the alirocumab and placebo groups, respectively).Specifically, in this study TEAEs were 75.8% vs 76.4%,treatment-emergent SAEs were 13.7% vs 14.3%, TEAEs leading to death were0.5% vs 0.9%, and TEAEs leading to discontinuation were 5.3% vs 5.1%,for alirocumab vs. placebo groups, respectively.

The most frequently reported SOC (and PT) in both treatment groups ofthe present study were: “infections and infestations”: 40.3% in thealirocumab group vs 34.3% in the placebo group (with influenza reportedin 11.1% vs 2.9% and urinary tract infection in 6.9% vs 0 in alirocumabvs placebo group respectively); “cardiac disorders”: 12.5% in thealirocumab group vs no case in the placebo group. Among the events sentto adjudication, events were confirmed for 6 patients presenting: 4 MI,1 heart failure requiring hospitalization and 5 ischemia driven coronaryrevascularization procedures; “nervous system disorders”: 11.1% in thealirocumab group vs 8.6% in the placebo group (with headache reported in5.6% vs 0 and dizziness 4.2% vs 0 in alirocumab vs placebo grouprespectively); and “musculoskeletal and connective tissue disorders”:16.7% in the alirocumab group vs 28.6% in the placebo group. No deathwas reported during the study in either group.

SAEs were reported by 11.1% patients in the alirocumab group and 11.4%in the placebo group. There is no particular clinical pattern among SAEspreferred terms which were individually reported. The most frequentlyreported SOC (system organ class) for SAEs is “cardiac disorders”.

Seven patients, 6 (8.3%) in the alirocumab group and 1 (2.9%) in theplacebo group experienced a treatment-emergent local injection sitereaction. These events were of mild intensity except one of moderateintensity. Two patients, one (1.4%) in the alirocumab group and one(2.9%) in the placebo group experienced neurocognitive disorders. Fourpatients, three (4.2%) in the alirocumab group and one (2.9%) in theplacebo group experienced ALT>3 x ULN. Two patients out of 71 analysed(2.8%, in comparison to 0 patients in the placebo group) experienced acreatine kinase level>3 x ULN. None of the events were serious or led totreatment discontinuation. TEAEs occurring in alirocumab and placebopatient groups were collected until the last patient visit at Week 52and are categorized in Table 36.

TABLE 36 TEAE safety analysis through week 52. % (n) of patients Allpatients on background of Alirocumab maximally tolerated statin ±Placebo 150 Q2W other LLT (N = 35) (N = 72) Nasopharyngitis 11.4% (4) 11.1% (8)  Influenza 2.9% (1) 11.1% (8)  Injection-site reaction 2.9%(1) 8.3% (6) Urinary tract infection 0 6.9% (5) Diarrhea 8.6% (3) 5.6%(4) Sinusitis 5.7% (2) 5.6% (4) Bronchitis 2.9% (1) 5.6% (4) Headache 05.6% (4) Fatigue 0 5.6% (4) Myalgia 8.6% (3) 4.2% (3) Nausea 5.7% (2)1.4% (1) Vertigo 5.7% (2) 1.4% (1) Dyspepsia 5.7% (2) 0 Increased BloodUric Acid 5.7% (2) 0 Rheumatoid arthritis 5.7% (2) 0

Among the events of interest no particular signal was detected for TEAErelated to neurological events, general allergic events and diabetes.

No relevant abnormality for PCSA was observed.

The present invention is not limited in scope by the specificembodiments described herein. Indeed, various modifications oftheinvention in addition to those described herein will become apparentto those skilled in the art from the foregoing description and theaccompanying figures. Such modifications are intended to fall within thescope of the appended claims.

Conclusion:

The following conclusions regarding patients with HeFH and high baselinelevels of LDL-C despite maximally tolerated statin with or withoutanother LLT can be drawn from the ODYSSEY HIGH FH study: 1)self-administered alirocumab produced significantly greater LDL-Creductions vs. placebo after 24 weeks, with absolute mean decreasingfrom baseline in LDL-C was −90.8 mg/dL at Week 24 with alirocumab versus−15.5 mg/dL with placebo, and resultant LDL-C levels of 107 mg/dL withalirocumab at Week 24 versus 182 mg/dL with placebo; 2) 32% ofalirocumab patients reached LDL-C<70 mg/dL despite baseline LDL-C>190mg/dL; 3) 57% of alirocumab patients achieved LDL-C<100 mg/dL at Week24; 4) alirocumab was generally well tolerated and TEAEs occurred in asimilar frequency in the alirocumab and placebo arms.

Example 5 Efficacy and Safety of the PCSK9 Monoclonal AntibodyAlirocumab vs Placebo in 1254 Patients with Heterozygous FamilialHypercholesterolemia (HeFH): Analyses Up to 78 Weeks from Four ODYSSEYTrials Background:

Previous studies have shown that only ˜20% of heterozygous familialhypercholesterolemia (HeFH) patients treated with lipid-loweringtherapies (LLTs) achieved pre-defined LDL-C target levels of ≤2.5 mmol/L[97 mg/dL]. The efficacy and safety of alirocumab vs placebo was studiedin 1254 HeFH pts on maximally-tolerated statin±other LLT from four,18-month, placebo-controlled ODYSSEY trials (FHI, FHII, HIGH FH, LONGTERM). This represents the single largest collection of patients withHeFH studied in a Phase 3 clinical trials program. A description of theLONG TERM study is set forth in Robinson et al., (2015) NEJM 372:16 pg1489-99, which is incorporated by reference herein in its entirety.

Methods:

Data were pooled by initial alirocumab dose. In FH I/II, patients withLDL-C levels≥1.81/2.59 mmol/L [70/100 mg/dL], depending on CV risk,received placebo (N=244) or alirocumab 75 mg Q2W (N=488); the alirocumabdose was increased to 150 mg Q2W at week 12 if LDL-C at week 8≥1.81mmol/L [70 mg/dL] (41.8% of patients). Separately, data was pooled fromHIGH FH (LDL-C≥4.14 mmol/L [160 mg/dL]) and the subset of patients withHeFH from LONG TERM (LDL-C≥1.81 mmol/L [70 mg/dL]), where patientsreceived placebo (N=180) or alirocumab 150 mg Q2W (N=342). All doseswere 1-mL subcutaneous (SC) injections. Data for change in LDL-C frombaseline was pooled through week 52.

Results:

Baseline LDL-C levels and changes from baseline with treatment are shownin Table 37. Compared to placebo, alirocumab reduced LDL-C by 49% and61% (p<0.0001) at week 12 for the 75 and 150 mg Q2W doses, respectively.At week 24, LDL-C reductions with alirocumab vs placebo were 56%(alirocumab 75 mg Q2W with a possible week 12 dose increase) and 59%(alirocumab 150 mg Q2VV), respectively (p<0.0001). For both doseregimens, despite high baseline LDL-C levels, LS mean LDL-C levels of ˜2mmol/L [77 mg/dL] were achieved by week 12 (Table 37), with reductionsmaintained through Week 52. Additional beneficial effects were observedin other parameters including non-HDL-C and Apo B.

In the individual studies to date, generally similar rates oftreatment-emergent adverse events (TEAEs) were observed in alirocumaband placebo-treated patients. Across placebo-controlled studies in theODYSSEY Program (patients both with and without HeFH), TEAEs (preferredterms) reported in ≥5% of alirocumab or placebo patients includenasopharyngitis (11.3% and 11.1% of alirocumab and placebo-treatedpatients, respectively), upper respiratory tract infection (URI) (6.1%vs 7.0%), injection site reaction (6.7% vs 4.8%), influenza (5.7% vs4.6%), headache (4.8% vs 5.2%) and arthralgia (4.0% vs 5.5%).

TABLE 37 Least-squares (LS) mean (SE) calculated LDL-C at week 12 (W12), week 24 (W 24) and week 52 (W 52) (intent-to-treat analyses)Alirocumab 75/150 mg Placebo (N = 244) Q2W (N = 488) Change % Change % %Pool of FHI Calculated from change Calculated from change difference andFHII LDL-C, baseline, from LDL-C, baseline, from versus studies† mmol/Lmmol/L baseline mmol/L mmol/L baseline placebo Baseline, 3.65 (0.08) — —3.66 (0.06) — — — mean (SE) W 12 3.80 (0.06) 0.14 (0.06) 5.4 (1.6) 2.04(0.04) −1.62 (0.04) −43.6 (1.1)* −49.0 (1.9)* W 24 3.86 (0.07) 0.21(0.07) 7.1 (1.7) 1.82 (0.05) −1.84 (0.05) −48.8 (1.2)* −55.8 (2.1)* W 523.90 (0.07) 0.25 (0 07) 8.8 (2.0) 1.85 (0.05) −1.81 (0.05) −48.2 (1.5)*−57.0 (2.5)* Pool of LONG TERM (HeFH patients only) and Alirocumab 150mg HIGH FH‡ Placebo (N = 180) Q2W (N = 342) Baseline, 3.99 (0.11) — —4.16 (0.09) — — — mean (SE) W 12 4.03 (0.08) −0.07 (0.08)  1.9 (1.7)1.75 (0.06) −2.35 (0.06) −58.8 (1.3)* −60.7 (2.1)* W 24 4.03 (0.08)−0.07 (0.08)  2.6 (1.9) 1.86 (0.06) −2.24 (0.06) −56.3 (1.4)* −58.9(2.4)* W 52 4.19 (0.10) 0.09 (0.10) 6.2 (2.5) 1.94 (0.07) −2.16 (0.07)−53.4 (1.8)* −59.6 (3.1)* †alirocumab dose 75 mg Q2W, increasing to 150mg Q2W at W 12 if LDL-C at W 8 ≥1.81 mmol/L; ‡alirocumab dose 150 mgQ2W; *p < 0.0001 vs placebo

Conclusions:

In this large cohort of 1254 pts with HeFH, alirocumab reduced meanLDL-C levels to <2 mmol/L [77 mg/dL] at week 24-52 of treatment, levelshitherto unobtainable with current LLTs.

1-92. (canceled)
 93. A method for treating hypercholesterolemia in apatient in need thereof having heterozygous familialhypercholesterolemia (heFH) and having a serum LDL-C concentration ofgreater than or equal to 70 mg/dL comprising administering, to thepatient, a therapeutically effective amount of antibody orantigen-binding fragment thereof which specifically binds human PCSK9and comprises an HCVR and an LCVR having the amino acid sequences of SEQID NOs: 1 and 6, respectively.
 94. The method of claim 93, wherein thepatient has taken a daily dose of statin for at least 4 weeks.
 95. Themethod of claim 94, wherein the statin is cerivastatin, pitavastatin,fluvastatin, lovastatin and/or pravastatin.
 97. The method of claim 93,wherein the patient has a history of cardiovascular disease.
 98. Themethod of claim 97, wherein the cardiovascular disease is coronary heartdisease, ischemic stroke or peripheral arterial disease.
 99. The methodof claim 93, wherein said serum LDL-C is 100 mg/dL or more.
 100. Themethod of claim 93, wherein said serum LDL-C is 130 mg/dL or more. 101.The method of claim 93, wherein said serum LDL-C is 140 mg/dL or more.102. The method of claim 93, wherein the antibody or fragment isadministered subcutaneously.
 103. The method of claim 93, wherein theantibody or fragment is alirocumab.